Cervical Dysplasia

Cervical Dysplasia

1 Overview

Summary and Quick Facts

  • Cervical dysplasia is the abnormal growth of the cells that line the surface of the cervix. A small percentage of women diagnosed with cervical dysplasia will go on to develop cervical cancer, which is one of the most preventable cancers.
  • In this protocol you will learn about factors that increase risk of cervical dysplasia and how cervical dysplasia is classified. The benefits and risks of currently available treatments will also be reviewed, and evidence concerning integrative interventions such as B vitamins and diindolylmethane (DIM), which have been studied in the context of cervical dysplasia, will be presented.
  • Women who opt for watchful waiting after a diagnosis of low-grade cervical dysplasia should adopt the healthy lifestyle choices and risk reduction measures presented in this protocol. It’s also important to follow ongoing screening recommendations, as advised by a healthcare provider. If the condition persists or worsens, active treatment can be instituted.

Cervical dysplasia is the abnormal growth of the cells that line the surface of the cervix. It is usually caused by the human papillomavirus (HPV). A small percentage of women diagnosed with cervical dysplasia will go on to develop cervical cancer, which is one of the most preventable cancers.

Integrative interventions like folate and green tea extract can help reduce the risk of cervical dysplasia and cervical cancer.

Risk Factors for Developing Cervical Dysplasia

  • HPV infection, a sexually transmitted infection found most frequently in teenagers and women in their early 20s
  • Oral contraceptives for longer than five years
  • Three or more full-term pregnancies and having the first full-term pregnancy before age 17

Testing for Cervical Dysplasia

  • Pap test: a procedure that involves removing a small sample of cervical cells, every three years for ages 21‒29, every five years for ages 30‒65
  • HPV test: every five years for ages 30‒65

Conventional Medical Treatments

  • Prevention through HPV vaccination (Cervarix, Gardasil, Gardasil 9)
  • Watchful waiting, as lower degrees of dysplasia frequently resolve without treatment
  • Cryotherapy, LEEP (loop electrosurgical excision procedure), and laser conization

Emerging Strategies

  • Biospectroscopy (the examination of the wavelength of light reflected from living tissue); DNA methylation testing of HPV; At-home HPV testing
  • HPV immunotherapy drug, VGX 3100; Carrageenan-based vaginal gel for prevention of high-risk HPV infection; High-dose vitamin D vaginal suppositories

Dietary and Lifestyle Changes

  • A greater consumption of fruits, vegetables, green tea, fiber, dietary vitamins A, C and E, beta-carotene, lutein, and folate protected against cervical dysplasia or cancer

Integrative Interventions

  • Folate and Vitamin B12: Low serum folate and vitamin B12 levels have been associated in multiple studies with an increased risk of cervical dysplasia and cervical cancer.
  • Vitamin E: Alpha-tocopherol levels were found to be lower in women with cervical abnormalities or cancer, and supplementation with vitamin E promoted reversal of cervical dysplasia in a randomized controlled trial.
  • Diindolylmethane (DIM) and Indole-3-Carbinol (I3C): DIM, derived from the digestion of I3C, appears to inhibit or prevent the progression from cervical dysplasia to cervical cancer.
  • Green Tea Extract: Women with cervical dysplasia who supplemented with green tea extract had nearly a 7 times higher response rate than women receiving no treatment.
  • Vitamin C: Women with the highest dietary vitamin C intake had an 80% reduced risk of cervical dysplasia compared with women whose vitamin C intake was lowest.

2 Introduction

Cervical dysplasia is abnormal growth of the cells that line the surface of the cervix. The cervix is the lower part of the uterus (womb) and is situated at the upper end of the vagina (ACOG 2014). Dysplastic cells can vary in their degree of abnormality from mild to severe, and dysplasia has several possible outcomes: it may disappear entirely, remain stable over time, or progress to cancer (Ho 2011; ACOG 2013a; Moore 2007). However, only a small percentage of women diagnosed with dysplasia will go on to develop cervical cancer, which is one of the most preventable cancers (ACOG 2013a; ACOG 2011a).

Cervical cancer used to be a common cause of death from cancer among American women. However, from 1955 to 1992, the cervical cancer death rate decreased by almost 70%, primarily due to increasing use of the Papanicolaou (Pap) test. This screening test can detect changes in the cervix before cancer develops or while cancer is still in its early stages, when treatment is generally most effective (ACS 2014a). Early diagnosis and treatment can prevent progression of dysplasia to cancer in as many as 90% of women (ACOG 2011b).

Most cases of cervical dysplasia and cervical cancer are associated with human papillomavirus (HPV) infection, which infects nearly all sexually active men and women at some point in their lives (CDC 2014). Fortunately, HPV types highly likely to cause cervical cancer can be vaccinated against (Fiks 2014; NCI 2012). However, at present, many women and girls are not vaccinated, possibly as a result of misperceptions about the vaccines or a lack of awareness because these vaccines are relatively new (Fiks 2014; Delere 2013; Etter 2012). This is unfortunate because HPV vaccination is highly effective in reducing risk of infection with high-risk HPV types (Ferris 2014; Luna 2013).

Low intake of several vitamins may increase risk of cervical cancer. Studies have shown that women with lower intakes of vitamins A, C, and E are at increased risk of cervical cancer (Kim 2010; Peng 1998). Also, women with low concentrations of B vitamins, especially folate, may have an increased risk of cervical dysplasia or cervical cancer (Butterworth 1982; Piyathilake 2004; Liu 1993; Butterworth 1992; Butterworth, Hatch 1992; Kwasniewska 2002; VanEenwyk 1992; Kwanbunjan 2006).

In this protocol you will learn about factors that increase risk of cervical dysplasia and how cervical dysplasia is classified. The benefits and risks of currently available treatments will also be reviewed, and evidence on integrative interventions such as B vitamins and diindolylmethane (DIM), which have been studied in the context of cervical dysplasia, will be presented. Novel and emerging therapies including new types of HPV vaccines will be discussed as well.

3 Background

Although a number of factors contribute to the development of cervical dysplasia, most cases involve exposure to the human papillomavirus (HPV), a common virus that also causes warts. HPV is spread through skin-to-skin contact, including sexual activity (ACS 2014b), and nearly all sexually active men and women will contract HPV at some point in their lives (Fiks 2014; ACS 2014b; CDC 2014). There are numerous strains of HPV. Some are much more likely to cause cellular abnormalities or cancer than others, and are denoted “high-risk” HPV types.

Cervical cancer rarely develops in women younger than age 20; most cases occur in midlife and in women under age 50. However, more than 20% of cervical cancer cases occur in women over 65. Most cases in women over 65 occur in those who did not undergo regular screening with Pap tests before age 65 (ACS 2014a). 

Cervical cancer usually develops over a period of several years (ACOG 2014). During this time, the cells on or around the cervix become abnormal. The cellular abnormalities that occur before cancer is present are usually called cervical intraepithelial neoplasia (CIN). “Intraepithelial” denotes that the changes occur within the cervical cells, and, in the case of precancerous growths of the cervix, “neoplasia” refers to uncontrolled cell growth.

Cervical dysplasia and cervical cancer are classified along a spectrum of increasing cervical cell abnormality. The goal of classification is to determine the degree to which the cervical cells have become abnormal, and whether treatment is needed, since lower degrees of dysplasia may resolve on their own without treatment. CIN is grouped into three categories (Storck 2014; OSU 2015):

  • CIN I (mild dysplasia)
  • CIN II (moderate dysplasia)
  • CIN III (severe dysplasia to carcinoma in situ)

The latest classification scheme is the Bethesda system (IARC 2014; NCI 2002). In the Bethesda system, low-grade squamous intraepithelial lesion (LSIL) encompasses CIN I; and high-grade squamous intraepithelial lesion (HSIL) includes CIN II and III (IARC 2014).

4 Risk Factors

Several risk factors for cervical dysplasia are well established. Risk factors interact and may be additive, so it is usually difficult to say that a given factor is responsible for any one case of cervical dysplasia or cancer (La Vecchia 2014; Arnheim Dahlstrom 2011; ACS 2014b).

HPV Infection

HPV is involved in virtually all cases of cervical dysplasia (Hogewoning 2003; Schiffman 2007; NCI 2012). The types of HPV that cause cervical dysplasia are usually sexually transmitted (ACS 2014b; Hogewoning 2003).

HPV comprises a group of more than 200 related viruses (NCI 2012). Each virus in the group is given a number, which is called an HPV type or strain (Kumar 2013). At least 12 HPV types are associated with cancer (NCI 2012). HPV type 16 is the most likely to cause cancer: it is closely associated with roughly 55–60% of cervical cancer cases in the world, and CIN II caused by HPV 16 may be less likely to regress than CIN II caused by other high-risk strains (ACOG 2013a; Castle 2009). HPV 18 is the next-most-likely to cause cancer, accounting for 10–15% of cervical cancer cases (ACOG 2013a). Eight other high-risk HPV strains (types 31, 33, 35, 45, 51, 52, 56, and 58) are associated with the great majority of other cases of cervical cancer (Wheeler 2009; de Sanjose 2010).

HPV infection occurs most frequently in teenagers and women in their early 20s (ACOG 2013a). Prevalence of HPV infection increases from age 14 to 24 but then gradually declines through age 59 (Dunne 2007). Young women, especially those 21 or younger, usually clear the infection by means of their immune response in an average of eight months (ACOG 2013a). Most associated cervical abnormalities will also spontaneously resolve among these women (Moore 2007; Fuchs 2007).

Other Risk Factors

Immunosuppression. Women receiving immunosuppressive therapy for autoimmune disease or cancer, or because of an organ transplant, are at increased risk of cervical dysplasia progressing to cervical cancer (Dugué 2013; ACOG 2014). Those with HIV/AIDS also have compromised immunity, which increases the risk for cervical dysplasia and cervical cancer (Davis 2001; Schafer 1991; Abraham 2013).

Smoking. Smoking increases the risk of many cancers, including cervical cancer (Silva 2014). Fortunately, research appears to show that quitting smoking reduces the risk of CIN III and cervical cancer (Roura 2014).

Diethylstilbestrol exposure. Daughters of women who took the synthetic hormone diethylstilbestrol (DES) during pregnancy are at increased risk for dysplasia and cervical cancer (NCI 2011a). DES has not been prescribed to pregnant women in the United States since 1971; thus, most DES-exposed women are currently beyond their childbearing years (Casey 2011).

Ethnicity. In the United States, women of different ethnicities have different degrees of risk of cervical cancer. Those most likely to develop cervical cancer are Hispanic women, followed by African-Americans, Asians and Pacific Islanders, and Whites, with the lowest risk found among American Indians and Alaskan natives (ACS 2014a).

Pregnancy-related risk factors. A woman’s pregnancy history appears to impact her risk for developing CIN and cervical cancer. For reasons not fully understood, three or more full-term pregnancies seem to increase the risk of developing cervical cancer. Additionally, women whose first full-term pregnancy occurred before age 17 are nearly twice as likely to develop cervical cancer later in life compared with women whose first pregnancy occurred at age 25 or older (ACS 2014b; Weppner 2014).

Oral contraceptives (birth control pills). Taking oral contraceptives for prolonged periods of time appears to increase the risk of cervical cancer. One study reported that cervical cancer risk doubled in women on birth control pills for more than five years, but found the risk returned to normal 10 years after they were discontinued (ACS 2014b).

Sexual history. Early sexual activity, during puberty or before age 18; having multiple sexual partners; and having a male partner who has had multiple sexual partners all increase a woman’s risk. Condoms provide some degree of protection from the spread of HPV as well as other sexually transmitted diseases when used consistently and properly (Weppner 2014; Zanotti 2014; ACOG 2014; ACS 2014b). One study found that condom use significantly promotes regression of cervical dysplasia, even of CIN II or higher (Hogewoning 2003).

Body weight. An observational study of 1125 women aged 18–65 years who had an HPV infection found that overweight women were at 25% increased risk of cervical cancer, while mildly obese women had 70% increased risk (Lee 2013). Also, overweight and obese women are at greater risk of dying from cervical cancer (Wee 2000).

Family history of cervical cancer. Women whose mother or sister had cervical cancer are at two to three times the risk of developing the disease themselves (ACS 2014b).

Chlamydia infection. Chlamydia is a sexually transmitted disease that often causes no symptoms. Women with a history of chlamydia infection appear to be at increased risk of cervical dysplasia and cervical cancer. A history of other sexually transmitted disease is also associated with increased risk of cervical dysplasia and cancer (ACS 2014b; Jensen 2014).

5 Signs and Symptoms

Cervical dysplasia does not have any specific signs or symptoms, though it can cause abnormal bleeding, spotting, or watery vaginal discharge. Menstrual bleeding can be abnormally heavy, and unusual bleeding may occur at other times, typically after intercourse. Advanced cervical cancer may cause pelvic pain, difficulty with urination, and leg swelling. Cervical cancer may spread to nearby organs or circulatory vessels, affecting their function (ACOG 2014; Zanotti 2014).

HPV Vaccination – Prevention of Cervical Dysplasia and Cervical Cancer

HPV vaccination confers a high degree of protection against cervical dysplasia and cervical cancer, and is a leading method of prevention. Males and females up to age 26 can be protected by receiving an HPV vaccination, and girls and boys as young as nine years of age are eligible for these vaccines (Xu 2005; Ferris 2014). Three HPV vaccines are approved by the US Food and Drug Administration (FDA): Cervarix, Gardasil, and Gardasil 9. The vaccinations are given in three injections over the course of six months (CDC 2011; Gardasil 2014a; Gardasil 2014b).

Cervarix protects against HPV types 16 and 18, which cause about 70% of cervical cancers (Goldie 2008; Cervarix 2012). Gardasil, known as Silgard in Europe, prevents infection from four HPV types: HPV 16 and 18, as well as HPV 6 and 11, which cause about 75% of cases of cervical cancer (Gardasil 2014c; McCormack 2014). In late 2014, the FDA approved Gardasil 9, which protects against nine HPV types: 6, 11, 16, 18, 31, 33, 45, 52, and 58. The five additional HPV types against which Gardasil 9 offers protection—31, 33, 45, 52, and 58—are not prevented by previously approved HPV vaccines. Gardasil 9 will protect against roughly 90% of cervical cancer cases (Simon 2015; FDA 2014; Joura 2015). HPV vaccination can also offer protection against anal, oropharyngeal, vulvar, vaginal, and penile cancers (NCI 2011b).

The vaccines work best when given before there is any contact with the HPV types against which they are meant to protect. Nevertheless, vaccination has been reported to be effective among women who are already sexually active. In 235 young women who were almost all (97%) sexually active before either receiving the complete set of HPV vaccinations, or being partially vaccinated, cervical cellular abnormalities were 65% less frequent in women who had received at least one HPV vaccination (Brogly 2014).

Some parents may be opposed to HPV vaccination for their children because they feel the vaccine would encourage risky sexual behavior (Soper 2006; Perkins 2010). However, a survey of 1243 females aged 15–24 years found that vaccination did not increase the likelihood of risky sexual behavior, and, in fact, vaccinated individuals were more likely to use condoms (Liddon 2012).

6 Diagnosis

The basic diagnostic tool for cervical dysplasia is the Pap test, a procedure that removes a small sample of cervical cells. A lab then analyzes the sample to determine if there are any abnormal cells (ACOG 2013c).

When results of a Pap test are abnormal, this does not mean that the patient has cancer, but rather that further evaluation is needed. Mildly abnormal cells sometimes may go away on their own. Additional tests after an abnormal Pap test may include a repeat Pap test, or a more detailed examination called colposcopy, which uses a low-power microscope to examine the cervix, and which is capable of viewing abnormalities that cannot be seen by the naked eye (Weppner 2014). During colposcopy, the doctor may sometimes also perform a biopsy. If precancerous changes are present, treatment will be based on several factors, such as age, the exact type of abnormal results, or how long abnormal cells have been present (ACOG 2013c; Brookner 1997). It is important that healthcare practitioners distinguish cervical dysplasia from other conditions that may present similarly, such as hyperkeratosis, metaplasia, warts, glandular epithelial abnormalities, and some types of cancer (Weppner 2014).

Cervical Screening Exams

Cervical cancer screening can detect changes in cervical cells that may lead to cancer. Screening includes the Pap test and, for some women, testing for HPV. The latest routine cervical cancer screening guidelines, released by the American Congress of Obstetricians and Gynecologists in 2013, read as follows (ACOG 2013b):

  • Cervical cancer screening should start at age 21 years; women and girls younger than this need not be screened.
  • Women aged 21–29 years should have a Pap test every three years.
  • Women aged 30–65 years should have a Pap test and an HPV test every five years. It is acceptable to have a Pap test alone every three years.
  • Women should no longer have cervical cancer screening after age 65, unless they have a history of moderate or severe dysplasia or cancer. If they have such history but have had either three negative Pap test results in a row, or two negative HPV and Pap co-test results in a row within the past 10 years, with the most recent test performed within the past five years, they need not resume screening. Once screening is stopped after age 65, it should not be resumed.
  • Women who have a history of cervical cancer, are infected with HIV, have a weakened immune system, or were exposed to DES before birth should not follow these routine guidelines. In these cases, women should seek guidance from their healthcare provider.
  • If a woman has an abnormal cervical cancer screening test result, additional testing or treatment may be indicated. Her healthcare provider will recommend when she can return to routine screening.
  • For women aged 30–65 years, the combination of a Pap test plus an HPV test can help predict whether dysplasia will be diagnosed in the next few years, even if the Pap test results are normal. If the results of both the HPV and Pap tests are normal, the chance that mild or moderate dysplasia will develop in the next four to six years is very low.
  • If a woman has had a hysterectomy that preserved her cervix, she may still need to undergo cervical cancer screening. Whether a woman needs to continue to have screening tests depends on why the hysterectomy was needed, whether the cervix was removed, and whether she has a history of moderate or severe dysplasia. Women in this situation should consult with their healthcare provider(s).

7 Conventional Treatment

Treatment of cervical dysplasia depends on the degree of dysplasia. Mild dysplasia, such as CIN I or LSIL, may go away without treatment, but careful follow-up at regular intervals, generally 6–12 months, is needed, and treatment should be performed if the changes do not go away or worsen over time (A.D.A.M. 2014).

Watchful Waiting

Lower degrees of dysplasia with lower-risk types of HPV frequently resolve without treatment, so some cases are managed with “watchful waiting” rather than active treatment (Ho 2011). If the condition persists or worsens, then active treatment can be instituted.

Women who opt for watchful waiting after a diagnosis of low-grade cervical dysplasia should adopt the healthy lifestyle choices and risk reduction measures presented in this protocol, and follow ongoing screening recommendations, as advised by their healthcare provider.

Active Treatment

Several active treatment options are available. These include ablation (cryotherapy or laser ablation), excision (including loop electrosurgical excision procedure [LEEP], cold knife conization, laser conization), and rarely, hysterectomy (Echelman 2012; Sauvaget 2013; Singh 2011).

Cryotherapy has been used successfully for the past fifty years, but use is declining, with other procedures such as laser ablation and LEEP being used with increasing frequency (Sauvaget 2013). Cryotherapy is most efficacious when used for smaller and less invasive cervical lesions. Cryotherapy does not treat cervical cancer, and is efficacious against 70–92% of CIN III cases (Echelman 2012). Cryotherapy involves the local application of a metal probe to the cervix, without touching the vagina, to administer a compressed gas such as nitrous oxide or carbon oxide to destroy the affected cervical tissue. It acts by decreasing the temperature locally, and causing crystallization and the breakage of cellular membranes (Sauvaget 2013; Singh 2011). Cryotherapy has a very low rate of complications, and adverse effects that may occur, such as vaginal discharge and cramps, are usually temporary and self-limited (McClung 2012).

LEEP, also known as loop excision of the transformation zone (LETZ) or large loop excision of the transformation zone (LLETZ), uses low current at high frequency and loops made of stainless steel or tungsten to excise the lesions. Some complications of LEEP include bleeding, incomplete removal of the lesion, and narrowing of the cervix, but advantages include low cost, high patient acceptance, and the possibility to retrieve samples for further laboratory analyses (Mayeaux 1993).

In a prospective study on 200 women, either cryotherapy or LEEP were reported to have good results in women with CIN, and LEEP was somewhat better for more severe lesions (Singh 2011).

Laser conization is another approach for excisional treatment. A study that examined the persistence of HPV genetic material after laser conization reported that the viral genome that existed before treatment regularly disappeared after the conization procedure (Kjellberg 2000).

8 Novel and Emerging Strategies

Emerging Testing Strategies

Biospectroscopy. Biospectroscopy is the examination of the wavelength of light reflected from specimens of living tissue or body fluids (Kelly 2011). This technique has been investigated as a screening tool for cervical cancer. A review of biospectroscopy as a screening tool for precancerous abnormalities of the cervix noted that it can identify different grades of dysplasia (Purandare 2013). Another study found that biospectroscopy was superior to the Pap test for identifying cervical abnormalities (Gajjar 2013). Further research is needed before biospectroscopy is incorporated into cervical screening programs.

DNA methylation testing. DNA methylation analysis is a promising new technology for HPV testing. Studies have found that the methylation status of certain sites within the DNA of HPV 16 are associated with CIN. This may allow a type of viral testing to predict actual risk for cervical abnormalities (Mir 2014). One study found that the combination of cervical cell testing (Pap test and colposcopy) and DNA methylation testing was highly effective for detecting high degrees of cervical dysplasia and cancer. DNA methylation testing plus colposcopy has been noted as a promising strategy for detecting cervical cancer and advanced CIN in HPV-positive women (De Strooper 2014).

At-home HPV testing. An at-home HPV test, called the UDoHPVTest, is available. This tests for HPV strains 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. The cost of the test is $140. Purchase price includes laboratory analysis and a physician review, online storage of the test results, and free counseling and support. The manufacturer states that the test is as accurate as those performed at approved clinical laboratories because it uses comparable methodology. The test can be purchased at https://www.udotest.com/test/udo-hpv-test (UDo HPV Test 2014).

Emerging Interventions

HPV immunotherapy. Positive results were obtained in a clinical trial of a new immunotherapeutic drug, VGX-3100, in women with biopsy-proven CIN II or CIN III associated with HPV types 16 or 18. The trial found that treatment with VGX-3100 resulted in significant regression of CIN II or CIN III to CIN I or no disease. In addition, the trial demonstrated significant clearance of HPV together with regression of cervical lesions in over 40% of treatment group participants, versus only 14.3% of control subjects. VGX-3100 works by eliciting a powerful immune response to specific vulnerable antigens expressed by HPV strains 16 and 18. Robust immune cell activity, as measured by CD4+ and CD8+ T-cell function and antibody titers, was detected in women who received VGX-3100, compared with those who received placebo (DDD 2014; Bagarazzi 2012; Gulzar 2004).

Carrageenan-based vaginal gel. Carrageenan is a compound extracted from edible red seaweeds; it is a complex sugar molecule that is widely used as a food additive. Carrageenan has been found to inhibit HPV infection in laboratory and animal studies (Yermak 1999; Rodríguez 2014). A randomized, controlled trial compared Carraguard, a carrageenan-based vaginal gel, plus condoms to placebo gel plus condoms for prevention of high-risk HPV infection. Among women who complied with use instructions for Carraguard, the prevalence of high-risk HPV infection was reduced by 38% (Marais 2011).

High-Dose Vitamin D Vaginal Suppositories

A trial compared vitamin D vaginal suppositories to a lactobacillus probiotic suppository for the treatment of cervical dysplasia. The vitamin D suppositories, which contained 12 500 IU vitamin D per dose, were used three nights per week for six weeks. The women in the trial suffered from either recurring chronic cervical fungal or bacterial infections, or CIN I or II dysplasia. The investigators reported that, compared with lactobacillus suppositories, vitamin D vaginal treatment showed “very good” anti-inflammatory effects, with patients reporting a high degree of satisfaction with the results of the vitamin D treatment, and only 7% experiencing persistence of fungal or bacterial infection. The authors concluded that vaginal vitamin D treatment had “good anti-dysplastic effects” against CIN I after six weeks. They cautioned that the safety of this vitamin D treatment during pregnancy is unknown (Schulte-Uebbing 2014).

9 Dietary and Lifestyle Considerations

Diet and dietary factors may be of value in preventing cervical dysplasia and the progression of cervical dysplasia to cancer. For instance, a study conducted in China showed that greater consumption of green tea and vegetables was associated with a reduced risk of cervical cancer or CIN II or III (Jia 2012). A hospital-based study found that higher dietary intakes of fiber and fruits and vegetables, as well as several micronutrients—vitamins C, E, and A, beta-carotene, lutein, and folate—were associated with reduced risk of cervical cancer among 239 cervical cancer cases and 979 controls (Ghosh 2008). In a large European study involving nearly 300 000 women, greater intake of fruits and vegetables was associated with lower risk of invasive squamous cervical cancer (Gonzalez 2011).

A more detailed study found that those with the highest dietary intake of vitamin A, beta-carotene, and vitamin C were at significantly lower risk for cervical cancer compared with those with the lowest intake. In this study, those in the high vitamin A or vitamin C dietary consumption group had a 64% lower risk of cervical cancer, while those in the high beta-carotene group had a 52% reduced risk. Higher total consumption of vitamins A, C, and E­—including dietary supplements—was associated with reduced risk of cervical cancer by 65%, 65%, and 47%, respectively (Kim 2010). A study that examined blood levels of carotenoid and tocopherol (vitamin E) compounds found that nearly all of them were lower in patients with cervical cancer (Peng 1998).

10 Integrative Interventions

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).

Multivitamin/Multinutrient Formulations

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). 

Vitamin E

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

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).

Vitamin C

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).

Green Tea

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.

A.D.A.M. Cervical Dysplasia. 2014. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002461/. Last accessed on October 29, 2014.

Abike F, Engin AB, Dunder I, Tapisiz OL, Aslan C, Kutluay L. Human papilloma virus persistence and neopterin, folate and homocysteine levels in cervical dysplasias. Archives of gynecology and obstetrics. Jul 2011;284(1):209-214.

Abraham AG, D'Souza G, Jing Y, Gange SJ, Sterling TR, Silverberg MJ, . . . Strickler HD. Invasive cervical cancer risk among HIV-infected women: a North American multicohort collaboration prospective study. Journal of acquired immune deficiency syndromes (1999). Apr 1 2013;62(4):405-413.

ACOG American College of Obstetricians and Gynecologists. Protect & Detect: What Women Should Know About Cancer. Available at: http://mail.ny.acog.org/website/ProtectDetect.pdf. 2011b. Last accessed 9/7/2014.

ACOG. American College of Obstetricians and Gynecologists. http://www.acog.org/Resources%20And%20Publications/. Resources & Publications page. Featured Committee Opinion: The Transition from Pediatric to Adult Health Care: Preventative Care for Young Women Aged 18 – 26 Years. 2013a. Last accessed 9/7/2014.

ACOG. American College of Obstetricians and Gynecologists. Cervical Cancer Screening. Available at: http://www.acog.org/Resources-And-Publications/Patient-Education-Pamphlets/Files/Cervical-Cancer-Screening. 2013c. Last accessed 9/7/2014.

ACOG. American College of Obstetricians and Gynecologists. Cervical Cancer Patient Education. Available at: http://www.acog.org/About-ACOG/ACOG-Districts/District-II/Cervical-Cancer-Patient-Education. 2011a. Last accessed 9/7/2014.

ACOG. American College of Obstetricians and Gynecologists. Cervical Cancer. Available at: http://www.acog.org/Patients/FAQs/Cervical-Cancer. 7/2014. Last accessed 9/28/2014.

ACOG. Patient education Fact Sheet. New Guidelines for Cervical Cancer Screening. American College of Obstetricians and Gynecologists. Available at: http://www.acog.org/~/media/For%20Patients/pfs004.pdf. 2013b. Last accessed 9/7/2014.

ACS. American Cancer Society. Learn About Cancer page. What are the key statistics about cervical cancer? Available at: http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-key-statistics. Last updated 8/15/2014a. Accessed 3/9/2015.

ACS. American Cancer Society. Cervical Cancer. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003094-pdf.pdf. Last updated 8/15/2014b. Last accessed 9/7/2014.

ACS. American Cancer Society. Find Support & Treatment page. Lycopene. Available at: http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/dietandnutrition/lycopene. Last updated 5/13/2010. Accessed 2/2/2015.

ACS. American Cancer Society. Find Support & Treatment page. Vitamin D. Available at: http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/herbsvitaminsandminerals/vitamin-d. Last updated 1/17/2013. Last accessed 9/28/2014.

ACS. American Cancer Society. Find Support & Treatment page. Vitamin A, Retinoids, and Provitamin A Carotenoids. Available at: http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/herbsvitaminsandminerals/vitamin-a-and-beta-carotene. Last updated 5/4/2012. Accessed 2/2/2015.

ACS. American Cancer Society. Learn About Cancer page. What are the key statistics about cervical cancer? Available at: http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-key-statistics. Last updated 8/15/2014a. Last accessed 9/7/2014.

Ahn WS, Yoo J, Huh SW, Kim CK, Lee JM, Namkoong SE, et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev. 2003;12(5):383-90.

Arnheim Dahlstrom L, Andersson K, Luostarinen T, Thoresen S, Ogmundsdottir H, Tryggvadottir L, . . . Dillner J. Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Dec 2011;20(12):2541-2550.

Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, . . . Sardesai NY. Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci Transl Med. Oct 10 2012;4(155):155ra138.

Bartley J. Vitamin D: emerging roles in infection and immunity. Expert review of anti-infective therapy. Dec 2010;8(12):1359-1369.

Bell MC, Crowley-Nowick P, Bradlow HL, Sepkovic DW, Schmidt-Grimminger D, Howell P, Mayeaux EJ, Tucker A, Turbat-Herrera EA, Mathis JM. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol. 2000;78(2):123-9.

Brogly SB, Perkins RB, Zepf D, Longtine J, Yang S. Human Papillomavirus Vaccination and Cervical Cytology in Young Minority Women. Sex Transm Dis. 2014 Aug;41(8):511-4.

Brookner CK, Agrawal A, Trujillo EV, Mitchell MF, Richards-Kortum RR. Safety analysis: relative risks of ultraviolet exposure from fluorescence spectroscopy and colposcopy are comparable. Photochemistry and photobiology. Jun 1997;65(6):1020-1025.

Butterworth CE, Jr. Effect of folate on cervical cancer. Synergism among risk factors. Annals of the New York Academy of Sciences. Sep 30 1992;669:293-299.

Butterworth CE, Jr., Hatch KD, Gore H, Mueller H, Krumdieck CL. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. The American journal of clinical nutrition. Jan 1982;35(1):73-82.

Butterworth CE, Jr., Hatch KD, Macaluso M, Cole P, Sauberlich HE, Soong SJ, . . . Baker VV. Folate deficiency and cervical dysplasia. JAMA: the journal of the American Medical Association. Jan 22-29 1992;267(4):528-533.

Casey PM, Long ME, Marnach ML. Abnormal cervical appearance: what to do, when to worry? Mayo Clinic proceedings. Mayo Clinic. Feb 2011;86(2):147-150; quiz 151.

Castle PE, Schiffman M, Wheeler CM, Solomon D. Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstetrics and gynecology. Jan 2009;113(1):18-25.

CDC. Centers for Disease Control and Prevention. HPV Vaccine Cervarix: What You Need to Know. Available at: http://www.cdc.gov/vaccines/hcp/vis/vis-statements/hpv-cervarix.pdf. 5/3/2011. Accessed 2/24/2015.

CDC. Centers for Disease Control and Prevention. Human Papillomavirus (HPV): Genital HPV Infection – Fact Sheeet. Available at: http://www.cdc.gov/std/hpv.stdfact-hpv.htm. Last updated 3/20/2014. Accessed 2/19/2015.

Cervarix. Available at: http://www.cervarix.ca. Copyright 2012. Last accessed 9/7/2014.

Chen DZ, Qi M, Auborn KJ, Carter TH. Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr. 2001;131(12):3294-302.

Cholujova D, Jakubikova J, Czako B, Martisova M, Hunakova L, Duraj J, . . . Sedlak J. MGN-3 arabinoxylan rice bran modulates innate immunity in multiple myeloma patients. Cancer immunology, immunotherapy : CII. Mar 2013;62(3):437-445.

Davis AT, Chakraborty H, Flowers L, Mosunjac MB. Cervical dysplasia in women infected with the human immunodeficiency virus (HIV): a correlation with HIV viral load and CD4+ count. Gynecologic oncology. Mar 2001;80(3):350-354.

DDD. Drug Discovery & Development. Inovio’s HPV Immunotherapy Hits Primary Endpoint. Available at: http://www.dddmag.com/news/2014/07/inovios-hpv-immunotherapy-hits-primary-endpoint. 7/23/2014. Accessed 10/6/2014.

de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Retrospective International Survey and HPV Time Trends Study Group. Lancet Oncol. 2010;11:1048–56.

De Strooper LM, Hesselink BA, Berkhof J, Meijer CJ, Snijders PJ, Steenbergen RD, Heideman DA. Combined CADM1/MAL methylation and cytology testing for colposcopy triage of high-risk HPV-positive women. Cancer Epidemiol Biomarkers Prev. 2014 [Epub ahead of print]

Delere Y, Bohmer MM, Walter D, Wichmann O. HPV vaccination coverage among women aged 18-20 years in Germany three years after recommendation of HPV vaccination for adolescent girls: results from a cross-sectional survey. Human vaccines & immunotherapeutics. Aug 2013;9(8):1706-1711.

Dugué PA, Rebolj M, Garred P, Lynge E. Immunosuppression and risk of cervical cancer. Expert Rev Anticancer Ther. 2013;13(1):29-42.

Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007;297:813–9.    

Echelman D, Feldman S. Management of cervical precancers: a global perspective. Hematology/oncology clinics of North America. Feb 2012;26(1):31-44.

Etter DJ, Zimet GD, Rickert VI. Human papillomavirus vaccine in adolescent women: a 2012 update. Current opinion in obstetrics & gynecology. Oct 2012;24(5):305-310.

FDA. U.S. Food and Drug Administration. FDA approves Gardasil 9 for prevention of certain cancers caused by five additional types of HPV. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm426485.htm. Last updated 12/11/2014. Accessed 2/19/2015.

Ferris D, Samakoses R, Block SL, Lazcano-Ponce E, Restrepo JA, Reisinger KS, et al. Long-term Study of a Quadrivalent Human Papillomavirus Vaccine. Pediatrics. 2014 [Epub ahead of print]

Fiks AG. Improving HPV vaccination rates.  LDI Issue Brief. 2014;19(1):1-4.

Flatley JE, McNeir K, Balasubramani L, Tidy J, Stuart EL, Young TA, Powers HJ. Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Oct 2009;18(10):2782-2789.

Fuchs K, Weitzen S, Wu L, Phipps MG, Boardman LA. Management of cervical intraepithelial neoplasia 2 in adolescent and young women. 2007. J Pediatr Adolesc Gynecol. 2007;20:269–74.

Fujii T, Takatsuka N, Nagata C, Matsumoto K, Oki A, Furuta R, . . . Yoshikawa H. Association between carotenoids and outcome of cervical intraepithelial neoplasia: a prospective cohort study. Int J Clin Oncol. Dec 2013;18(6):1091-1101.

Gajjar K, Ahmadzai AA, Valasoulis G, Trevisan J, Founta C, et al. Histology Verification Demonstrates That Biospectroscopy Analysis of Cervical Cytology Identifies Underlying Disease More Accurately than Conventional Screening: Removing the Confounder of Discordance. PLoS ONE. 2013; 9(1): e82416.

Ganguly C, Dutta K, Sanyal U, Roy C, Basu PS, Das S. Response of Cervical Intra-epithelial Lesions to Vitamin E Supplementation - A Preliminary Report. Asian Pac J Cancer Prev. 2001;2(4):305-308.

Garcia-Iglesias T, Del Toro-Arreola A, Albarran-Somoza B, Del Toro-Arreola S, Sanchez-Hernandez PE, Ramirez-Duenas MG, . . . Daneri-Navarro A. Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC cancer. 2009;9:186.

Gardasil. About Gardasil page: FAQs About Gardasil.  Available at: http://www.gardasil.com/about-gardasil/faqs-about-gardasil/. Copyright © 2014c. Accessed 10/6/2014.

Gardasil. HPV & Your Child. Available at: http://www.gardasil.com/. Copyright © 2014a. Accessed 2/24/2015.

Gardasil. Patient Information about Gardasil®9. Available at: http://www.gardasil9.com/. 12/2014b. Accessed 2/24/2015.

Ghosh C, Baker JA, Moysich KB, Rivera R, Brasure JR, McCann SE. Dietary intakes of selected nutrients and food groups and risk of cervical cancer. Nutrition and cancer. 2008;60(3):331-341.

Goldie SJ, O'Shea M, Diaz M, Kim SY. Benefits, cost requirements and cost-effectiveness of the HPV16,18 vaccine for cervical cancer prevention in developing countries: policy implications. Reproductive health matters. Nov 2008;16(32):86-96.

Gonzalez CA, Travier N, Lujan-Barroso L, Castellsague X, Bosch FX, Roura E, . . . Riboli E. Dietary factors and in situ and invasive cervical cancer risk in the European prospective investigation into cancer and nutrition study. International journal of cancer. Journal international du cancer. Jul 15 2011;129(2):449-459.

Gulzar N, Copeland KF. CD8+ T-cells: function and response to HIV infection. Current HIV research. Jan 2004;2(1):23-37.

Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55(3):224-36.

Ho GY, Einstein MH, Romney SL, Kadish AS, Abadi M, Mikhail M, et al. 2011. Risk factors for persistent cervical intraepithelial neoplasia grades 1 and 2: managed by watchful waiting. J Low Genit Tract Dist. 2011;15(4):268-75.

Hogewoning CJ, Bleeker MC, van den Brule AJ, Voorhorst FJ, Snijders PJ, Berkhof J, . . . Meijer CJ. Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: a randomized clinical trial. International journal of cancer. Journal international du cancer. Dec 10 2003;107(5):811-816.

Hosono S, Matsuo K, Kajiyama H, Hirose K, Suzuki T, Kawase T, et al. Association between dietary calcium and vitamin D intake and cervical carcinogenesis among Japanese women. Eur J Clin Nutr. 2010;64(4):400-9.

Hwang JH, Kim MK, Lee JK. Dietary supplements reduce the risk of cervical intraepithelial neoplasia. Int J Gynecol Cancer. 2010;20(3):398-403.

IARC. International Agency for Research on Cancer. Chapter 2: An introduction to cervical intraepithelial neoplasia (CIN). Available at: http://screening.iarc.fr/colpochap.php?chap=2. 2014. Last accessed 9/7/2014.

Jensen KE, Thomsen LT, Schmiedel S, Frederiksen K, Norrild B, van den Brule A, Iftner T, Kjær SK. Chlamydia trachomatis and risk of cervical intraepithelial neoplasia grade 3 or worse in women with persistent human papillomavirus infection: a cohort study. Sex Transm Infect. 2014 [Epub ahead of print]

Jia Y, Hu T, Hang CY, Yang R, Li X, Chen ZL, et al. Case-control study of diet in patients with cervical cancer or precancerosis in Wufeng, a high incidence region in China. Asian Pac J Cancer Prev. 2012;13(10):5299-302.

Joura EA, Giuliano AR, Iversen O-E, Bouchard C, Mao C, Mehlsen J, . . . Luxembourg A. A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women. New England Journal of Medicine. 2015;372(8):711-723.

Kelly JG, Trevisan J, Scott AD, Carmichael PL, Pollock HM, Martin-Hirsch PL, Martin FL. Biospectroscopy to metabolically profile biomolecular structure: a multistage approach linking computational analysis with biomarkers. Journal of proteome research. Apr 1 2011;10(4):1437-1448.

Kim J, Kim MK, Lee JK, Kim JH, Son SK, Song ES, Lee KB, Lee JP, Lee JM, Yun YM. Intakes of vitamin A, C, and E, and beta-carotene are associated with risk of cervical cancer: a case-control study in Korea. Nutr Cancer. 2010;62(2):181-9.

Kim SY, Kim JW, Ko YS, Koo JE, Chung HY, Lee-Kim YC. Changes in lipid peroxidation and antioxidant trace elements in serum of women with cervical intraepithelial neoplasia and invasive cancer. Nutr Cancer. 2003;47(2):126-30.

Kjellberg L, Wadell G, Bergman F, Isaksson M, Angstrom T, Dillner J. Regular disappearance of the human papillomavirus genome after conization of cervical dysplasia by carbon dioxide laser. American journal of obstetrics and gynecology. Nov 2000;183(5):1238-1242.

Kohaar I, Kumar J, Thakur N, Hussain S, Niyaz MK, Das BC, et al. Homocysteine levels are associated with cervical cancer independent of methylene tetrahydrofolate reductase gene (MTHFR) polymorphisms in Indian population. Biomarkers. 2010;15(1):61-8.

Kumar S, Jena L, Daf S, Mohod K, Goyal P, Varma AK. hpvPDB: An Online Proteome Reserve for Human Papillomavirus. Genomics & informatics. Dec 2013;11(4):289-291.

Kwanbunjan K, Saengkar P, Cheeramakara C, Tangjitgamol S, Chitcharoenrung K. Vitamin B12 status of Thai women with neoplasia of the cervix uteri. Southeast Asian J Trop Med Public Health;37 Suppl 3. 2006:178-83.

Kwasniewska A, Tukendorf A, Gozdzicka-Jozefiak A, Semczuk-Sikora A, Korobowicz E. Content of folic acid and free homocysteine in blood serum of human papillomavirus-infected women with cervical dysplasia. European journal of gynaecological oncology. 2002;23(4):311-316.

Langers I, Renoux V, Reschner A, Touze A, Coursaget P, Boniver J, . . . Jacobs N. Natural killer and dendritic cells collaborate in the immune response induced by the vaccine against uterine cervical cancer. European journal of immunology. Dec 2014;44(12):3585-3595.

La Vecchia C, Boccia S. Oral contraceptives, human papillomavirus and cervical cancer. European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP). Mar 2014;23(2):110-112.

Lee GJ, Chung HW, Lee KH, Ahn HS. Antioxidant vitamins and lipid peroxidation in patients with cervical intraepithelial neoplasia. J Korean Med Sci. 2005;20(2):267-72.

Lee JK, So KA, Piyathilake CJ, Kim MK. Mild obesity, physical activity, calorie intake, and the risks of cervical intraepithelial neoplasia and cervical cancer. PLoS One. 2013;12;8(6):e66555.

Liddon NC, Leichliter JS, Markowitz LE. Human Papillomavirus Vaccine and Sexual Behavior Among Adolescent and Young Women. Am J Prev Med. 2012;42:44–52.

Liu JJ, Ward RL. Folate and one-carbon metabolism and its impact on aberrant DNA methylation in cancer. Advances in genetics. 2010;71:79-121.

Liu T, Soong SJ, Wilson NP, Craig CB, Cole P, Macaluso M, Butterworth CE, Jr. A case control study of nutritional factors and cervical dysplasia. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Nov-Dec 1993;2(6):525-530.

Luna J, Plata M, Gonzalez M, Correa A, Maldonado I, Nossa C, . . . Saah A. Long-term follow-up observation of the safety, immunogenicity, and effectiveness of Gardasil in adult women. PloS one. 2013;8(12):e83431.

Marais D, Gawarecki D, Allan B, Ahmed K, Altini L, Cassim N, Gopolang F,et al. The effectiveness of Carraguard, a vaginal microbicide, in protecting women against high-risk human papillomavirus infection. Antivir Ther. 2011;16(8):1219-26.

Mayeaux EJ, Jr., Harper MB. Loop electrosurgical excisional procedure. The Journal of family practice. Feb 1993;36(2):214-219.

McClung EC, Blumenthal PD. Efficacy, safety, acceptability and affordability of cryotherapy: a review of current literature. Minerva ginecologica. Apr 2012;64(2):149-171.

McCormack PL. Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine (Gardasil®): A Review of Its Use in the Prevention of Premalignant Anogenital Lesions, Cervical and Anal Cancers, and Genital Warts. Drugs. Jul 2014;74(11):1253-1283.

Mir S, Domjahn B, Ault KA. Investigating human papillomavirus 16 methylation as a biomarker for high-grade cervical intraepithelial neoplasia. Obstet Gynecol. 2014;123 Suppl 1:184S-5S.

Moore K, Cofer A, Elliot L, Lanneau G, Walker J, Gold MA. Adolescent cervical dysplasia: histologic evaluation, treatment, and outcomes. American journal of obstetrics and gynecology. Aug 2007;197(2):141.e141-146.

Myung SK, Ju W, Kim SC, Kim H. Vitamin or antioxidant intake (or serum level) and risk of cervical neoplasm: a meta-analysis. BJOG. 2011;118(11):1285-91.

NCI. National Cancer Institute. Bethesda 2001: A Revised System for Reporting Pap Test Results Aims to Improve Cervical Cancer Screening. Available at: http://www.cancer.gov/newscenter/newsfromnci/2002/bethesda2001. 4/23/2002. Last accessed 9/28/2014.

NCI. National Cancer Institute. Diethylstilbestrol (DES) and Cancer. Available at: http://www.cancer.gov/cancertopics/factsheet/Risk/DES. Last updated 10/5/2011a. Last accessed 9/7/2014.

NCI. National Cancer Institute. HPV and Cancer. Available at: http://www.cancer.gov/cancertopics/factsheet/Risk/HPV. 3/15/2012. Last accessed 9/7/2014.

NCI. National Cancer Institute. Human Papillomavirus (HPV) Vaccines. Available at: http://www.cancer.gov/cancertopics/factsheet/prevention/HPV-vaccine. 12/29/2011b. Last accessed 9/28/2014.

OSU. Ohio State University webpage. About Cervical Cancer. Available at: http://cancer.osu.edu/cancer-specialties/cancer-care-and-treatment/gynecologic-cancers/cervical-cancer. Copyright 2015. Accessed 2/2/2015.

Palan PR, Mikhail MS, Goldberg GL, Basu J, Runowicz CD, Romney SL. Plasma levels of beta-carotene, lycopene, canthaxanthin, retinol, and alpha- and tau-tocopherol in cervical intraepithelial neoplasia and cancer. Clin Cancer Res. 1996;2(1):181-5.

Palan PR, Mikhail MS, Shaban DW, Romney SL. 2003. Plasma concentrations of coenzyme Q10 and tocopherols in cervical intraepithelial neoplasia and cervical cancer. Eur J Cancer Prev. 2003;12(4):321-6.

Palan PR, Woodall AL, Anderson PS, Mikhail MS. Alpha-tocopherol and alpha-tocopheryl quinone levels in cervical intraepithelial neoplasia and cervical cancer. Am J Obstet Gynecol. 2004;190(5):1407-10.

Pathak S, Bajpai D, Banerjee A, Bhatla N, Jain SK, Jayaram HN, Singh N. Serum one-carbon metabolites and risk of cervical cancer. Nutrition and cancer. 2014;66(5):818-824.

Pathak S, Bhatla N, Singh N. Cervical cancer pathogenesis is associated with one-carbon metabolism. Molecular and cellular biochemistry. Oct 2012;369(1-2):1-7.

Peng YM, Peng YS, Childers JM, Hatch KD, Roe DJ, Lin Y, Lin P. Concentrations of carotenoids, tocopherols, and retinol in paired plasma and cervical tissue of patients with cervical cancer, precancer, and noncancerous diseases. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Apr 1998;7(4):347-350.

Perkins RB, Pierre-Joseph N, Marquez C, Iloka S, Clark JA. Parents' opinions of mandatory human papillomavirus vaccination: does ethnicity matter? Women's health issues: official publication of the Jacobs Institute of Women's Health. Nov-Dec 2010;20(6):420-426.

Piyathilake CJ, Henao OL, Macaluso M, Cornwell PE, Meleth S, Heimburger DC, Partridge EE. Folate is associated with the natural history of high-risk human papillomaviruses. Cancer research. Dec 1 2004;64(23):8788-8793.

Purandare NC, Trevisan J, Patel II, Gajjar K, Mitchell AL, Theophilou G, Valasoulis G, et al. Exploiting biospectroscopy as a novel screening tool for cervical cancer: towards a framework to validate its accuracy in a routine clinical setting. Bioanalysis. 2013;5(21):2697-711.

Radtke AL, Quayle AJ, Herbst-Kralovetz MM. Microbial products alter the expression of membrane-associated mucin and antimicrobial peptides in a three-dimensional human endocervical epithelial cell model. Biology of reproduction. Jun 2012;87(6):132.

Rodríguez A, Kleinbeck K, Mizenina O, Kizima L, Levendosky K, Jean-Pierre N, et al. In vitro and in vivo evaluation of two carrageenan-based formulations to prevent HPV acquisition. Antiviral Res. 2014 Aug;108:88-93.

Romney SL, Duttagupta C, Basu J, Palan PR, Karp S, Slagle NS, et al. Plasma vitamin C and uterine cervical dysplasia. Am J Obstet Gynecol. 1985;151(7):976-80.

Roura E, Castellsague X, Pawlita M, Travier N, Waterboer T, Margall N, . . . Riboli E. Smoking as a major risk factor for cervical cancer and pre-cancer: results from the EPIC cohort. International journal of cancer. Journal international du cancer. Jul 15 2014;135(2):453-466.

Sasagawa T, Takagi H, Makinoda S. Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. Dec 2012;18(6):807-815.

Sauvaget C, Muwonge R, Sankaranarayanan R. Meta-analysis of the effectiveness of cryotherapy in the treatment of cervical intraepithelial neoplasia. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. Mar 2013;120(3):218-223.

Schafer A, Friedmann W, Mielke M, Schwartlander B, Koch MA. The increased frequency of cervical dysplasia-neoplasia in women infected with the human immunodeficiency virus is related to the degree of immunosuppression. American journal of obstetrics and gynecology. Feb 1991;164(2):593-599.

Schiff MA, Patterson RE, Baumgartner RN, Masuk M, van Asselt-King L, Wheeler CM, Becker TM. Serum carotenoids and risk of cervical intraepithelial neoplasia in Southwestern American Indian women. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Nov 2001;10(11):1219-1222.

Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. Sep 8 2007;370(9590):890-907.

Schulte-Uebbing C, Schlett S, Craiut I, Antal L, Olah H. Chronical cervical infections and dysplasia (CIN I, CIN II): Vaginal vitamin D (high dose) treatment: A new effective method? Dermatoendocrinol. 2014;6(1):e27791.

Sepkovic DW, Raucci L, Stein J, Carlisle AD, Auborn K, Ksieski HB, . . . Bradlow HL. 3,3'-Diindolylmethane increases serum interferon-gamma levels in the K14-HPV16 transgenic mouse model for cervical cancer. In vivo (Athens, Greece). Mar-Apr 2012;26(2):207-211.

Sepkovic DW, Stein J, Carlisle AD, Ksieski HB, Auborn K, Bradlow HL. Diindolylmethane inhibits cervical dysplasia, alters estrogen metabolism, and enhances immune response in the K14-HPV16 transgenic mouse model. Cancer Epidemiol Biomarkers Prev. 2009;18(11):2957-64.

Silva C, Almeida EC, Côbo Ede C, Zeferino VF, Murta EF, Etchebehere RM. A retrospective study on cervical intraepithelial lesions of low-grade and undetermined significance: evolution, associated factors and cytohistological correlation. Sao Paulo Med. 2014;132(2):92-6.

Simon S. FDA Approves Gardasil 9 HPV Vaccine. American Cancer Society webpage. Available at: http://www.cancer.org/cancer/news/news/fda-approves-gardasil-9-hpv-vaccine. 1/8/2015. Accessed 2/20/2015.

Singh A, Arthur B, Agarwal V. LEEP Verses Cryotherapy in CIN. Journal of obstetrics and gynaecology of India. Aug 2011;61(4):431-435.

Slattery ML, Abbott TM, Overall JC Jr, Robison LM, French TK, Jolles C, et al. Dietary vitamins A, C, and E and selenium as risk factors for cervical cancer. Epidemiology. 1990;1(1):8-15.

Soper D. Reducing the health burden of HPV infection through vaccination. Infectious diseases in obstetrics and gynecology. 2006;2006 Suppl:83084.

Storck S. NIH (National Institutes of Health) MedlinePlus webpage. Cervical dysplasia. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001491.htm. Last updated 2/24/2014. Accessed 2/2/2015.

Sun J. Vitamin D and mucosal immune function. Current opinion in gastroenterology. Nov 2010;26(6):591-595.

Sundström H, Yrjänheikki E, Kauppila A. Low serum selenium concentration in patients with cervical or endometrial cancer. Int J Gynaecol Obstet. 1984;22(1):35-40.

Tomita LY, Longatto Filho A, Costa MC, Andreoli MA, Villa LL, Franco EL, Cardoso MA. Diet and serum micronutrients in relation to cervical neoplasia and cancer among low-income Brazilian women. International journal of cancer. Journal international du cancer. Feb 1 2010;126(3):703-714.

UDo HPV Test. 2014. https://www.udotest.com/test/udo-hpv-test. Last accessed 9/7/2014.

Van Belle TL, Gysemans C, Mathieu C. Vitamin D in autoimmune, infectious and allergic diseases: a vital player? Best practice & research. Clinical endocrinology & metabolism. Aug 2011;25(4):617-632.

Van den Bergh JM, Guerti K, Willemen Y, Lion E, Cools N, Goossens H, . . . Smits EL. HPV vaccine stimulates cytotoxic activity of killer dendritic cells and natural killer cells against HPV-positive tumour cells. Journal of cellular and molecular medicine. Jul 2014;18(7):1372-1380.

VanEenwyk J, Davis FG, Bowen PE. Dietary and serum carotenoids and cervical intraepithelial neoplasia. International journal of cancer. Journal international du cancer. Apr 22 1991;48(1):34-38.

VanEenwyk J, Davis FG, Colman N. Folate, vitamin C, and cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev. 1992;1(2):119-24.

Verhoeven V, Renard N, Makar A, et al. Probiotics enhance the clearance of human papillomavirus-related cervical lesions: a prospective controlled pilot study. Eur J Cancer Prev. 2013;22(1):46-51.

Wang JT, Ding L, Jiang SW, Hao J, Zhao WM, Zhou Q, . . . Zhang L. Folate deficiency and aberrant expression of DNA methyltransferase 1 were associated with cervical cancerization. Current pharmaceutical design. 2014;20(11):1639-1646.

Wee CC, McCarthy EP, Davis RB, Phillips RS. Screening for cervical and breast cancer: is obesity an unrecognized barrier to preventive care? Ann Intern Med. May 2 2000;132(9):697-704.

Weinstein SJ, Ziegler RG, Selhub J, Fears TR, Strickler HD, Brinton LA, . . . Stolley PD. Elevated serum homocysteine levels and increased risk of invasive cervical cancer in US women. Cancer causes & control: CCC. May 2001;12(4):317-324.

Weppner DM, Alvero R. Ferri's Clinical Advisor. Cervical Dysplasia. Available at: www.clinicalkey.com. Copyright © 2014. Accessed 7/11/2014.

Wheeler CM, Hunt WC, Joste NE, Key CR, Quint WG, Castle PE. Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst. 2009;101:475–87.

Xu J, Dennehy P, Keyserling H, Westerman LE, Wang Y, Holman RC, . . . Jiang B. Serum antibody responses in children with rotavirus diarrhea can serve as proxy for protection. Clinical and diagnostic laboratory immunology. Feb 2005;12(2):273-279.

Yermak IM, Kim Y, Titlynov E, Isakov V, Solov'eva T. Chemical structure and gel properties of carrageenans from algae belonging to the Gigartinaceae and Tichocarpaceae, collected from the Russian Pacific coast. Journal of Applied Phycology. 1999;11(1):41-48.

Zanotti K, Singh S. Cervical malignancy/dysplasia. First Consult. Available at: www.clinicalkey.com. Last updated 1/7/2014. Accessed 7/11/2014. 2014.

Zhang X, Dai B, Zhang B, Wang Z. Vitamin A and risk of cervical cancer: a meta-analysis. Gynecol Oncol. 2012;124(2):366-73.

Ziegler RG, Weinstein SJ, Fears TR. Nutritional and genetic inefficiencies in one-carbon metabolism and cervical cancer risk. The Journal of nutrition. Aug 2002;132(8 Suppl):2345s-2349s.