~Cervical Dysplasia - Reversing the Road to Cervical Cancer

~Cervical Dysplasia - Reversing the Road to Cervical Cancer
Reprinted with permission of Life Extension®.

Cervical dysplasia is characterized by abnormal (dysplastic) cells in the cervix. Extending into the vagina, the cervix is the lowest part of the uterus. Although cervical dysplasia does not produce symptoms itself, it is potentially dangerous because it can progress to cervical cancer, the second-most common type of cancer in women, especially among younger women (Nicol 2005; Marshall 2003; Rock 2000).

Since the introduction of the Pap smear in 1941, the death rate from cervical cancer has dropped significantly because of early detection of cervical dysplasia. In developing countries, where Pap smears are not as common as in industrialized countries, cervical dysplasia is reported to be the leading cause of cancer in women (Potischman 1996). Worldwide, cervical cancer accounts for 11.6 percent of cancers in women (Giuliano 1998; Rock 2000).

In more than 99 percent of cases, cervical cancer and cervical dysplasia are caused by the human papillomavirus (HPV), the virus that causes genital warts (Yeo 2000). HPV is very common: the lifetime risk of a woman contracting genital HPV is estimated to be 80 percent (Bekkers 2004). It is transmitted through sexual intercourse. The virus may be present without symptoms, making it possible for carriers to transmit it unknowingly.

The vast majority of women with HPV will not develop cervical dysplasia or cancer (Marshall 2003; Giuliano 1998). There are many variations of the virus, and some forms carry a higher risk for the development of cancer than others, especially HPV16 and HPV18 (Liu 1993). HPV is often difficult to detect because it rarely causes symptoms. Only about 1 percent of women with HPV have visible genital warts (Wright 2004), which adds to the importance of regular Pap smears.

The goal of cervical dysplasia treatment is reducing the risk of its progression to cervical cancer. This risk reduction may be accomplished through dietary modification, supplementation, and possibly by chemoprevention through the use of medical or chemical modifiers (Rock 2000; Pereira 2004; Maissi 2004). Fortunately, there is hope on the horizon. Because of lifestyle changes, the prevalence of Pap smears, and exciting research into HPV vaccines, cervical cancer rates are expected to continue dropping in the industrialized world.

Classification And Screening For Cervical Dysplasia

Cervical dysplasia is commonly referred to as cervical intraepithelial neoplasia (CIN). It is often classified by the degree of penetration of abnormal cells into the tissue lining (epithelium):

  • CIN I describes the involvement of the basal third of the epithelium.
  • CIN II involves the basal two thirds of the epithelium.
  • CIN III involves more than two thirds of the epithelium.

A diagnosis of cervical dysplasia does not necessarily mean that cervical cancer will develop. In fact, up to 74 percent of women with mild CIN will naturally regress to normal within five years (Holowaty 1999). Of those cases that do progress, only a minority of women will actually develop cancer.

  • Only 1 percent of women with CIN I who experience progression will progress to severe dysplasia or worse (Holowaty 1999).

  • Among patients with CIN II, 16 percent will advance to severe dysplasia within two years and 25 percent within five years.

  • An overall progression rate of severe dysplasia (CIN III) to cervical cancer has been observed in 12 to 32 percent of patients (Arends 1998; McIndoe 1984).

Pap smears are the standard tool used to screen women for cervical dysplasia or cancer. During a Pap smear, cells are scraped from the cervix and then evaluated microscopically. About 5 to 7 percent of Pap smears yield abnormal findings (Jones 2000).

One major problem with screening is poor follow-up testing among women with abnormal Pap smears. In most cases, an abnormal Pap smear requires a follow-up test in a few months. However, an estimated 10 to 61 percent of women with abnormal Pap smears do not undergo follow-up testing (Shinn 2004). Factors associated with noncompliance include an elementary education, prior surgery, additional diseases, consumption of medications for chronic conditions, and family illness (Bornstein 2004).

In general, according to the American Cancer Society’s 2002 screening guidelines:
Women should begin cervical cancer screening no later than three years after beginning vaginal intercourse but no later than 21 years of age.

Cervical cancer screening should be performed annually with regular Pap tests or every two years with liquid-based Pap tests.

A woman 30 years of age or older with three consecutive normal Pap smears may elect to be screened every two to three years.

Women who have undergone hysterectomy can elect to discontinue Pap smears if the surgery was not performed to treat cervical cancer or precancer. Women with an intact cervix post hysterectomy should undergo screening until at least age 70.

A woman older than age 70 may choose to discontinue Pap smear screening after three prior normal Pap smears and no abnormal results in the preceding 10 years.
Risk Factors For Progression

While it may take years for cervical dysplasia to progress to cancer, the cancer can quickly spread throughout the body once established. If left untreated, cervical cancer has a relatively high mortality rate, although the survival rate for properly treated early-stage cervical dysplasia and cervical cancer is high.

Early symptoms of cervical cancer, such as altered vaginal discharge and abnormal vaginal bleeding, are rare. Advanced cervical cancer may present with pelvic, back, or leg pain, leaking of urine or feces from the vagina, loss of appetite, weight loss, and bone fracture.

Not all cases of cervical dysplasia progress into cancer (Marshall 2003). Rather, it appears that certain factors may hasten the progression from cervical dysplasia to cervical cancer:

  • Decreased methylation. DNA hypomethylation is significantly associated with the grade of CIN (Fowler 1998; Goodman 2001).

  • Multiple HPV types. One study showed a significantly increased risk of CIN in women with several HPV subtypes (Ho 1998).

  • Viral load. A high level of the virus is a significant risk factor for CIN (Li 2004; Schlecht 2003; Dalstein 2003; Ylitalo 2000; Josefsson 2000; Ho 1998; Romney 1997; Flores 2005).

  • High-risk HPV variants. Certain virus strains are an independent risk factor for cervical dysplasia (Thomson 2000; Liu 1995).

  • Persistence of HPV infection. Persistent infection with HPV increases the risk of cervical cancer (Giuliano 1997; Romney 1997).

  • Smoking. Smoking is a serious independent risk factor for advanced cervical dysplasia (Palan 1991). Passive cigarette smoking via a spouse also has been associated with a higher incidence of high-grade squamous intraepithelial lesions (Tay 2004). Women with abnormal Pap smears absolutely should avoid smoking.

  • Obesity. In one large study, fewer overweight and obese women (78 percent in each group) underwent cervical cancer screening with Pap smears (Wee 2000). Because this group of women have a higher mortality rate for cervical cancer compared with women of normal weight, special attention should be paid to increasing screening among overweight and obese women.

  • Number of sexual partners. The number of sexual partners increases the risk of cervical dysplasia (Thomson 2000), perhaps by increasing the chances of encounters with HPV strains.

  • Multiple pregnancies. Multiple pregnancies have been cited as a possible risk factor for cervical dysplasia (Munoz 2002; Liu 1993; Thomson 2000).

  • Lower socioeconomic status and lack of Pap smears. Women with a lower educational level may avoid follow-up Pap smears (Bornstein 2004). Additionally, those with lower socioeconomic status may lack access to appropriate health care.

  • Diethylstilbestrol (DES). DES was given to expectant mothers from the late 1930s until 1970 to prevent early delivery. However, many mothers were unaware that the drug was being administered to them; sometimes it was given with a vitamin supplement. Unfortunately, it resulted in increased cervical cancer in female offspring. Current research regarding the use of DES focuses on the effects of the drug in granddaughters and grandsons of those who received it (Centers for Disease Control 2005).

  • Compromised immune function. Women with medical conditions that affect the immune system are at greater risk for cervical dysplasia. These conditions include HIV, systemic lupus erythematosus, and transplanted organs (Duerr 2001; Robinson 2002; Bernatsky 2004; Malouf 2004; Ozsaran 1999).

  • Other sexually transmitted diseases. One study concluded that the presence of other sexually transmitted diseases, such as Herpes simplex virus and Chlamydia trachomatis, can cause dysplasia to progress to cervical cancer (Smith 2002a; Smith 2002b). However, other studies failed to show an association between these sexually transmitted diseases and cervical cancer progression (Castle 2003; Tran-Thanh 2003).

Conventional Treatment Of Cervical Dysplasia And Cancer

Cervical Dysplasia

The success rate of treating early-stage cervical dysplasia is extremely high. During treatment, a physician will attempt to remove the abnormal cells through a variety of methods, including cryotherapy, or freezing the cells to destroy them.

Alternatively, a procedure called loop electrosurgical excision may be performed. During this procedure, a thin wire loop with an electrical current is used to remove a cone-shaped piece of tissue. Women treated with loop excision are likely to convert to HPV-negative status, which eliminates the risk for HPV-related cervical dysplasia and cancer (Aschkenazi-Steinberg 2005). If a larger area of the cervix contains abnormal cells, a gynecologist may perform a surgical procedure called cervical conization to remove all the abnormal cells.

In case of high-grade CIN, or if previous surgeries left too little cervical tissue, a hysterectomy may be recommended (Das 2005). In rare advanced cases, all the organs of the pelvis can be removed in a procedure called pelvic exenteration. Except for hysterectomy or pelvic exenteration, the surgical choices typically allow a woman to carry a child in future pregnancies.

Cervical Cancer

Sometimes radiation or chemotherapy is required in addition to surgery for cancers that are recurrent or have spread beyond the pelvis. Survival rates depend on the stage of the cancer. With treatment, five-year survival rates are 80 to 85 percent for cervical and uterine tumors, 60 to 80 percent for tumors involving the upper part of the vagina, 30 to 50 percent for tumors still retained in the pelvis, and 14 percent when cancer has invaded the bladder or rectum or metastasized outside the pelvis.

Vaccines and Antivirals: Hope for the Future?

Recently, media attention has focused on possible vaccines for cervical cancer. Although these vaccines are still in the development stage, a vaccine for low-grade dysplasia will likely be available soon (Stanley 2003).

HPV Vaccines Are Available Now

The CDC: HPV vaccines are given as three shots to protect against HPV infection and HPV-related diseases. Two vaccines (Cervarix and Gardasil) have been shown to protect against most cervical cancers in women. One vaccine (Gardasil) also protects against genital warts and has been shown to protect against cancers of the anus, vagina and vulva. Both vaccines are available for females. Only Gardasil is available for males.

HPV vaccines offer the greatest health benefits to individuals who receive all three doses before having any type of sexual activity. That’s why HPV vaccination is recommended for preteen girls and boys at age 11 or 12 years. (http://www.cdc.gov/hpv/vaccine.html)

Vaccines may soon offer hope of dramatically reducing the rate of HPV infection and in turn, the rates of cervical dysplasia and cervical cancer.

Learnings So Far

  • Cervical dysplasia is a proliferation of abnormal cells in the lining of the cervix.

  • Cervical dysplasia left untreated may develop into cervical cancer.

  • Cervical cancer is the second-most common type of cancer in women.

  • Early detection and treatment of cervical cancer are highly effective. The mortality rate for untreated cervical cancer is 95 percent within two years.

  • The survival rate for properly treated early-stage cervical cancers is between 70 and 100 percent.

  • Virtually 100 percent of cases of cervical dysplasia and cervical cancer are the result of HPV.

  • The lifetime risk of contracting a genital HPV infection is about 80 percent in women.

  • Not all women with HPV will develop dysplasia or cancer of the cervix.

  • Only 1 percent of women with HPV develop external warts. Dysplasia does not cause symptoms.

  • The lack of symptoms in dysplasia, infrequent screening, and various risk factors sometimes allow cervical dysplasia to develop into cervical cancer.

  • The Pap smear is the standard screening tool to detect dysplasia.

Nutrient Support For A Healthy Cervix

Since as far back as 1981, statistically significant differences in levels of vitamins A, C, and beta carotene have been noted between women with cervical dysplasia and healthy controls (Romney 1981; Wassertheil-Smoller 1981). Other nutrients studied in cervical dysplasia include folate, zinc, and vitamins B6, B12, and E. Changes in diet and nutritional supplementation can reduce the odds of developing cervical cancer (Marshall 2003; Gagandeep 2003; Friedman 2005).

Vitamin A. Vitamin A deficiency has been observed in women with various grades of CIN, and higher levels of vitamin A have been shown to help reduce the risk of progression to cervical cancer (Kwasniewska 1996; Yeo 2000; Liu 1993; Shannon 2002; Volz 1995). Vitamin A deficiencies have been linked to CIN among Southwestern American Indian women (Yeo 2000) and HIV-positive women (French 2000). Vitamin A also may have a protective effect for black women in the early stages of CIN (Kanetsky 1998).

In two studies of women with CIN, a 3-fold to 4.5-fold higher risk of cervical cancer development was seen in those with a low level of vitamin A (Nagata 1999; Wylie-Rosett 1984). More severe stages of cervical dysplasia were associated with an even lower level of vitamin A (Kwasniewska 1996). Conversely, high levels of vitamin A were associated with cervical dysplasia regression, particularly in those who were HPV16-positive (Liu 1995).

B vitamins. Numerous studies have also shown vitamin B deficiencies among women with cervical dysplasia.

Vitamin B1. In women with high- and low-grade squamous intraepithelial lesions of the cervix, the level of vitamin B1 was decreased in those with CIN. Progression of cervical dysplasia was associated with reduced levels of vitamin B1 (Hernandez 2003).

Vitamin B2. Low levels of vitamin B2 have been associated with an increased risk of low- and high-grade CIN (Liu 1993; Hernandez 2003). Interestingly, vitamin B2 deficiency has been associated with oral contraceptive use.

Vitamin B6. Cervical squamous intraepithelial lesions have been associated with a vitamin B6 deficiency (Ramaswamy 1984).

Vitamin B12. Low levels of vitamin B12 have been associated with both low- and high-grade squamous cervical lesions, as well as with HPV persistence (Hernandez 2003; Sedjo 2002; Goodman 2001). However, another study did not show an association between vitamin B12 and women who were either positive or negative for HPV (Sedjo 2003).

Folic Acid. Insufficient intake of folate is associated with increased risk for cervical dysplasia (Liu 1993; Kwanbunjan 2004; Buckley 1992; Grio 1993; Kwasniewska 1997; Weinstein 2001; Butterworth 1992; Ziegler 1986; Hernandez 2003; Goodman 2001). Interestingly, folate deficiency can be misdiagnosed as cervical dysplasia because their characteristics are similar (Zarcone 1996; Butterworth 1982).

Other theories to explain the connection between folate deficiency and cervical dysplasia include the increased demand for folate associated with pregnancy and oral contraceptive use (Potischman 1991; Butterworth 1982). This increased demand results in a folate deficiency in the cervical tissue, which could increase the risk of CIN (Piyathilake 2000).

One study suggests that folate deficiency could cause chromosomal damage, such as that seen in cervical cancer, as a result of impaired DNA synthesis or repair (Christensen 1996). Additional studies state that folate status may be involved in early stages of CIN but not in advanced disease (Potischman 1996; Butterworth 1992).

Vitamin C. An increased incidence of cervical dysplasia has been found with low levels of vitamin C (ascorbic acid) in several studies (Romney 1985; Liu 1993; Potischman 1996; Palan 1996; Kwasniewska 1998; Buckley 1992; de Vet 1991; Kwasniewska 1996; Lee 2005).

Antioxidants. In general, antioxidant status has been closely linked to cervical dysplasia. Many studies have found low levels of antioxidants in women with various grades of cervical dysplasia. These antioxidants include alpha-tocopherol, gamma-tocopherol, beta-carotene, lutein, lycopene, canthaxanthin, alpha- and beta-cryptoxanthin, coenzyme Q10, and glutathione (Palan 2003; Palan 2004; Palan 1991; Palan 1996; Giuliano 1997; Kim 2003; Ho 1998; Goodman 1998). However, the relationship between reduced antioxidant levels and cervical dysplasia is poorly understood. It could be that lower antioxidant levels contribute to development of the condition, or conversely, the disease might cause reduced antioxidant levels as the body seeks to fight the disease. In either case, patients with cervical dysplasia should consider supplementing with a robust antioxidant program.

Minerals. Cervical dysplasia patients have also been found to have abnormal levels of minerals, including copper, selenium, and zinc. Studies have shown that patients with cervical dysplasia and invasive cancers have lower levels of selenium and zinc and a higher level of copper (Kim 2003; Grail 1986; Rybnikov 1985; Liu 1995). Ferritin, an iron-storing protein, has been shown to have a protective effect against cervical dysplasia (Amburgey 1993).

Cumin. Finally, the spice cumin has been demonstrated in animal studies to reduce the likelihood of developing cervical cancer (Gagandeep 2003).

Melatonin. Melatonin may help suppress rapid cell growth and mutation, but this association is still being studied, and some studies have found melatonin to have no effect on certain cancer lines (Anisimov 2000; Panzer 1998). Nevertheless, melatonin is commonly used by patients with cervical dysplasia (Greenlee 2004). One study found that melatonin inhibits the growth of cervical cancer cells in laboratory cultures after 48 hours of treatment (Chen 1995).

Researchers are also looking at variations in melatonin levels among patients with cervical dysplasia. One study revealed lowered melatonin secretion in endometrial cancer patients but not in those with squamous cervical cancer (Karasek 2000).

Working To Fight Off Cervical Cancer

It is fortunate that most cases of cervical dysplasia will not progress to cancer, and if detected, cervical dysplasia is relatively easily treated. If cervical dysplasia progresses to cervical cancer, the treatment options are similar: cryosurgery (i.e., freezing the cancer) or loop electrosurgical excision. If they are treated early enough, it is possible for many women with early-stage cervical cancer to bear children. Advanced cancer that has spread beyond the cervix can require hysterectomy, radiation treatment, or chemotherapy.

While an abnormal Pap smear is reason to carefully adhere to any regimen of follow-up testing and treatment under the care of a physician, studies show certain nutrients also have an ability to fight cervical cancer. Research on cervical cancer has focused on agents that have low toxicity and display activity against HPV-positive cell lines (Vlastos 2003). The following chemical compounds are under investigation:

Indole-3-carbinol. Indole-3-carbinol, a plant compound from cruciferous vegetables like broccoli and cauliflower, has been studied in connection with the management of CIN. The effectiveness of this plant compound has been documented in small clinical trials (Stanley 2003; Bell 2000). Indole-3-carbinol reduces the formation of 16 alpha-hydroxyestrone, a suspected carcinogen, which in high levels is associated with a greater risk of cervical cancer (Sepkovic 2001).

Vitamin A. Retinoids, the natural and synthetic forms of vitamin A, inhibit the growth of epithelial cells through transforming growth factor beta (Comerci 1997). Additionally, retinoids have been reported to support the differentiation of cells (thereby preventing abnormal cervical cancer cells), as well as to affect the immune response of cells (Ahn 1997; Darwiche 1994).

Coenzyme Q10. Coenzyme Q10 is used by cells for growth and maintenance and as an antioxidant. Some studies have suggested coenzyme Q10 stimulates the immune system. Low levels have been found in certain cancers. Studies suggest the usefulness of coenzyme Q10 in adjuvant therapy in cervical cancer, especially in conjunction with alpha- and gamma-tocopherols (Palan 2003).

Green tea. A study of 51 patients showed a reduction of 69 percent of cervical dysplasia lesions in patients who received green tea extracts as either an ointment or capsule (Ahn 2003).

Blueberry Extract. Blueberries may slow the growth of cancer cells. In 2001, University of Mississippi researchers conducting in-vitro tests found that blueberry and strawberry extracts were remarkably successful in slowing the growth of two aggressive cervical cancer cell lines and two fast-replicating breast cancer cell lines, with the blueberry extract performing best against the cervical cancer cells (Wedge 2001).

Melatonin. In animal studies, this hormone is reported to prevent the proliferation of errant cells as well as to help prevent mutation of cells and the breakage of chromosomes (Anisimov 2000). In lab studies, growth of cervical cancer cells diminished within 48 hours of administration of melatonin (Chen 1995).

Turmeric (curcumin). Turmeric is effective in regulating cell development, cell division, and programmed cell death (Nagai 2005; Chen 2005; Ramachandran 2005; Sharma 2005; Seo 2005; Fang 2005; Weber 2005; Karunagaran 2005; Furness 2005; Tilak 2004; Surh 1999). With regard to cervical cancer, turmeric affects the transcription of the high-risk variant HPV18 as well as other cellular transcription responses (Prusty 2005). Finally, turmeric combined with the chemotherapeutic agent vinblastine is effective against resistant cervical cancer (Limtrakul 2004; Chearwae 2004).

Life Extension Suggestions

High potency multivitamin that includes the following:

  • Vitamin A: 500 IU acetate and 4500 IU beta-carotene daily

  • Vitamin C: 1000 – 3000 mg daily

  • Folate (preferably as L-methylfolate): 400 – 1000 mcg daily

  • Vitamin B6 (preferably as pyridoxal-5-phosphate): 75 – 105 mg daily

  • Vitamin B12: 300 – 600 mcg daily

  • Selenium: 200 mcg daily

  • Zinc: 30 mg daily

  • Melatonin: 3 – 10 mg nightly

  • Curcumin (highly absorbable): 400 – 800 mg daily

  • Vitamin E (as high gamma tocopherol mix with sesame lignans): 359 mg daily

  • Indole-3-carbinol: 80 – 160 mg daily

  • Coenzyme Q10 (as ubiquinol): 100 – 200 mg daily with food

  • Blueberry extract: 500 – 2000 mg daily

  • Green tea extract: 725 mg daily

Safety Caveats

An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:


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Vitamin E

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References below.
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