Folate and Vitamin B12
Folate deficiency has been known for decades to play a role in cervical dysplasia and cervical cancer, and in certain situations supplementation of folate has been shown to have a positive impact on the course of these conditions (Butterworth 1982; Piyathilake 2004; Liu 1993; Butterworth 1992; Butterworth, Hatch 1992; Kwasniewska 2002; VanEenwyk 1992). A 2011 study evaluated the relationship between degrees of cervical dysplasia and folate in 122 women. All women with cervical cell abnormalities ranging from low grade to high grade had significantly lower serum folate levels than healthy controls (Abike 2011). Folate is important to the body’s methylation status, which is part of what is sometimes referred to as “one-carbon metabolism.” This is an essential factor in the proper functioning of DNA, and thus possibly in cancer formation (Liu 2010).
Two studies from one research group found that lower levels of folate and vitamin B12 were associated with HPV infection (Pathak 2014; Pathak 2012). One study found that women whose serum homocysteine levels were higher than 6.3 µmol/L had about three times greater odds of having invasive cervical cancer than women whose homocysteine levels were lower. The exact cause of elevated homocysteine was unknown in this study, though the authors speculated it could have resulted from B vitamin inadequacy or a genetic cause (Weinstein 2001; Ziegler 2002). In 50 women infected with HPV types 16 or 18, significantly lower serum folate and higher serum homocysteine levels were found in those women with high-grade cervical dysplasia (CIN III) (Kwasniewska 2002). In a different study, serum homocysteine levels were found to be significantly higher in cervical cancer and dysplasia cases compared with controls (Kohaar 2010).
Methylation and folate was the subject of a study that enlisted 238 women, with findings ranging from normal cervical tissue, CIN I or II/III, to cervical carcinoma. In this study, as the severity of cervical abnormalities increased, levels of serum folate decreased. In a laboratory section of the study, folate helped regulate a protein that methylates DNA. The authors concluded that low serum folate contributes to the formation of cervical cancer (Wang 2014). Another study examined methylation of DNA and one-carbon metabolism in 308 women. Some of these women did not have any cervical abnormalities, some had CIN I to III, and others had invasive cervical cancer. Lower folate was significantly associated with high-risk HPV infection and with CIN or invasive cervical cancer. Overall, methylation of DNA was significantly lower in women with invasive cervical cancer compared to other groups. The authors concluded that folate may play a role in modulating the risk of cervical cancer, perhaps by influencing high-risk HPV infection (Flatley 2009).
A study compared the vitamin B12 levels of women with low- and high-grade cervical dysplasia to those of women with normal Pap tests. Serum vitamin B12 was significantly higher in women with normal Pap tests, compared to those with both low- and high-grade cervical dysplasia. Low vitamin B12 levels were significantly associated with low-grade (4-fold increased risk) and high-grade (3.5-fold increased risk) cervical dysplasia, compared with high levels of serum vitamin B12 (Kwanbunjan 2006).
A rigorous review evaluating data from 22 studies on over 10 000 women revealed that higher dietary intake of vitamins B12, C, E, and beta-carotene was significantly protective against cervical neoplasia (Myung 2011). One study evaluated whether dietary supplements would benefit patients with high-risk HPV infections and decrease risk of cervical cancer developing in these patients. The study group comprised 1096 women aged 18–65 years who were followed up from 2006 through 2010. Multivitamins, vitamins A, C, E, and calcium were all significantly associated with a lower risk of CIN II or III. The women who took multivitamins had a lower HPV viral load (level of viral infection) and had significantly lower prevalence of CIN I, II, or III (Hwang 2010).
In a randomized controlled trial, 53 women with CIN I and 19 with CIN II received 444 IU alpha-tocopherol (a form of vitamin E) daily for one year, while 35 and 15 women in each category received placebo. In the CIN I group, there was regression in a significant 74% of women who received vitamin E compared to just 17% in the placebo group. In the CIN II group, there was regression in 37% of women compared to 26% in the placebo group; and among the CIN II-placebo group, 20% of cases progressed to a higher-grade abnormality compared to just 5% in the CIN II-vitamin E group (Ganguly 2001). A study in 72 women was conducted to determine the relationship between blood levels of alpha-tocopherol and cervical dysplasia/cancer. Among this group of women, 37 had CIN, 14 had cervical cancer, and 21 had normal Pap tests. The investigators found that alpha-tocopherol levels were significantly lower in women with cervical abnormalities (Palan 2004). In a previous study, the same investigators compared 235 women who had either cervical cancer, dysplasia, or a normal Pap test. The investigators found the average alpha-tocopherol level was significantly lower in the women with dysplasia or cervical cancer (Palan 1996). Another study compared serum levels of alpha-tocopherol and coenzyme Q10 (CoQ10) in women with normal Pap tests (48 women) to those with CIN I to III (157 women) or cervical cancer (25 women). They found that plasma concentrations of alpha-tocopherol, gamma-tocopherol, and CoQ10 were significantly lower in those with CIN and cervical cancer (Palan 2003). Higher blood levels of the vitamin E compounds alpha- and gamma-tocopherol were associated with a nearly 50% reduction in the risk of CIN III (Tomita 2010).
Diindolylmethane (DIM) and Indole-3-Carbinol (I3C)
Diindolylmethane (DIM) is a compound derived from the digestion of indole-3-carbinol (I3C), a small amount of which is present in cruciferous vegetables such as broccoli, Brussels sprouts, cabbage, and kale. DIM appears to inhibit or prevent the progression from cervical dysplasia to cervical cancer (Sepkovic 2012; Sepkovic 2009; Higdon 2007).
A randomized controlled trial treated 30 women with biopsy-proven CIN II or III with either placebo or I3C (200 or 400 mg per day) for 12 weeks. If persistent CIN was diagnosed by cervical biopsy at the end of the study, a LEEP procedure was performed on the cervix. The investigators found that none of the patients in the placebo group had complete regression of CIN. In contrast, four of eight patients in the 200 mg/day arm and four of nine patients in the 400 mg/day arm had complete regression (Bell 2000).
A mouse study was conducted to determine whether cervical cancer development could be inhibited by DIM. The mice were a strain bred to have increased cancer susceptibility; they were implanted with estrogen pellets to stimulate cancer growth. About half the mice were fed a normal diet and the other half were fed a diet supplemented with DIM for 12 weeks. The investigators found that DIM delayed or inhibited the progression from cervical dysplasia to cervical cancer (Sepkovic 2009). Another study of DIM was conducted on mice and three cervical cancer cell lines. The investigators found that DIM could destroy cervical cancer cells in both the mice and cell cultures (Chen 2001).
Vitamin D and Calcium
A number of studies have reported that vitamin D improves immune response, helps control inflammation, and may help the body fight infections (ACS 2013a; Bartley 2010; Van Belle 2011; Sun 2010). Researchers evaluated 405 women, 333 with invasive cervical cancer and 72 with CIN III, and compared them with 2025 healthy women of a similar age. They found that women who had a diet high in milk, yogurt, and fish were much less likely to have invasive cancer, while women whose diet was high in tofu and green leafy vegetables had a moderately decreased risk of CIN III. These researchers concluded that higher dietary calcium and vitamin D intake was associated with lower cervical cancer risk among this group of women (Hosono 2010).
Selenium and Zinc
A study of Korean women with cervical dysplasia and cervical cancer assessed serum selenium and zinc levels. Among the study group, 28 had CIN and 36 had invasive cervical cancer. These women were compared to 44 healthy women. Women with CIN or cancer had significantly lower selenium and zinc levels (Kim 2003).
In another study, 37 women with cervical cancer were found to have lower serum concentrations of selenium than a control group of healthy women (Sundström 1984). In a study that compared 266 women with cervical cancer with 408 controls, the women with higher dietary intake of selenium had a slightly reduced risk of cervical cancer (Slattery 1990).
Vitamin A is important for healthy mucous membranes. Because the cervical lining is a mucous membrane, vitamin A may be an important factor in regulating cervical tissue as well as the immunity of the cervical microenvironment (Radtke 2012). A rigorous study of the literature was conducted to examine dietary or serum vitamin A levels and the risk of cervical cancer. The review collated data from 11 articles on dietary vitamin A and four articles on serum vitamin A levels, which included a total of 12 136 participants. The researchers found that both higher vitamin A intake and serum vitamin A levels were associated with a lower risk of cervical cancer (Zhang 2012). Another study evaluated whether vitamin A could lower the risk of cervical cancer. It found that lower vitamin A intake was strongly associated with higher cervical cancer risk (Kim 2010).
Carotenoids are fat-soluble phytonutrients and antioxidants. Perhaps the best known carotenoid is beta-carotene, which the body can convert to vitamin A. Lycopene is another well-known carotenoid (ACS 2012; ACS 2010). Others include lutein, zeaxanthin, and alpha-carotene. In a large Brazilian study, higher serum concentrations of lycopene were associated with decreased risk of CIN I, CIN III, and cervical cancer. Specifically, risk of CIN I fell by 47%, while that of CIN III decreased 52%, and risk of cervical cancer plummeted by 82% for women with the highest serum lycopene concentrations compared with those whose lycopene levels were lowest (Tomita 2010). Another study found that blood levels of carotenoids, including beta-carotene and lycopene, were significantly lower in women with CIN and cervical cancer (Palan 1996). A study examining the relationship of carotenoid levels with the regression or progression of CIN found that among women who did not smoke, those with higher levels of the carotenoids lutein and zeaxanthin had a 1.25-fold higher likelihood of regression (Fujii 2013). Another study looked at the relationship between dietary and serum lycopene in 102 women with CIN compared to healthy controls and found that those with the lowest serum lycopene levels had a 3.5- to 4.7-fold higher risk of CIN compared with those whose levels were highest. Similar results were found for dietary lycopene intake: women with the lowest intake had 4.6- to 5.8-fold higher risk of CIN (VanEenwyk 1991). In Native American women with CIN II/III, compared to healthy controls, as blood levels of the carotenoids alpha-carotene, lutein, and zeaxanthin increased, the risk of CIN II/III decreased. Those who had the highest lutein and zeaxanthin intake had a 60% reduced risk of CIN (Schiff 2001). Another study, which examined levels of nutrients in both blood and cervical samples from women with cervical cancer, CIN, and uterine conditions, concluded that maintaining adequate blood and tissue concentrations of beta-carotene may be essential to preventing cervical dysplasia and cervical cancer (Peng 1998).
A survey of dietary intake and serum vitamin C levels in 58 patients diagnosed with CIN and 86 patients without cervical disease found that serum concentrations of vitamin C were 25% lower in the CIN group compared with the control group. The investigators concluded there is a possible correlation between cervical dysplasia and antioxidant metabolism (Lee 2005). Another study found that women with the highest dietary vitamin C intake had an 80% reduced risk of CIN compared with women whose vitamin C intake was lowest. This same research team previously found that women with the lowest dietary vitamin C intake had a 3.7- to 6.4-fold higher risk of CIN compared with those whose dietary vitamin C intake was highest (VanEenwyk 1992; VanEenwyk 1991). In a comparison of vitamin C levels between women with normal cervical test results and women with abnormal Pap tests, the average vitamin C level was significantly lower in the women with evidence of cervical abnormalities (Romney 1985).
In one study, 104 women with CIN II, III, or cervical cancer were compared to 936 healthy women. In this population, green tea intake of several cups per week, over a two-year period, was associated with 40% reduced odds of cervical cancer (Jia 2012).
A combination of green tea extract as a topically applied ointment and green tea extract supplement capsules, containing epigallocatechin gallate (EGCG) and other polyphenols, was the subject of a study in women with HPV-infected cervical lesions. Ninety women with cervical abnormalities (chronic cervical inflammation, mild dysplasia, moderate dysplasia and severe dysplasia) were included in the study, with 51 of them receiving the green tea treatment. Some women applied the green tea extract ointment to their cervix twice a week, some took an oral green tea extract, and some women used both the oral extract and the cervical ointment. An additional 39 women acted as controls, receiving no treatment. Overall, a 69% response rate was noted for treatment with green tea extracts, compared with a 10% response rate in the untreated group. The authors concluded that green tea extracts in the form of an ointment or capsule are effective for treating cervical lesions (Ahn 2003).
In a six-month clinical study on 54 women with HPV-positive LSIL, probiotics were found to increase the clearance of cervical cellular abnormalities and HPV infection. The women were divided into two treatment groups: a daily probiotic drink or placebo. At the end of the treatment period, the women who consumed the probiotic drink were twice as likely to have exhibited clearance of their cervical cell abnormalities. In addition, HPV infection was cleared in 29% of the women in the probiotic group versus only 19% in the placebo group. While allowing that more studies are needed, the investigators remarked, “If confirmed, this would represent an entirely new option to manage cervical cancer precursors” (Verhoeven 2013).
Enzymatically Modified Rice Bran
Natural killer (NK) cells are components of the immune system that help combat viral infections and tumor formation. NK cells are involved in the clearance of HPV infection and establishing an immune response to HPV vaccination (Van den Bergh 2014; Langers 2014; Sasagawa 2012). Some evidence suggests NK cell activity may be altered in cancerous and pre-cancerous cervical lesions (Garcia-Iglesias 2009). Enzymatically modified rice bran has been shown to enhance NK cell activity (Cholujova 2013), and may benefit women with cervical dysplasia or those wishing to prevent this condition. However, enzymatically modified rice bran has yet to be studied specifically in the context of cervical dysplasia or cervical cancer, so more research is needed before the potential benefits for women in these situations are established.