Management of Cervical Dysplasia: A Naturopathic Approach

By Kelly Parcell, ND and Steve Parcell, ND

The Papanicolaou test (Pap smear) is one of the most effective cancer screening tests available.  It can detect premalignant lesions and has contributed to the decline in cervical cancer morbidity and mortality in the United States since its development in 1941. Pap smears in women who have smears categorized as low-grade squamous intraepithelial lesions (LGSIL) or atypical squamous cells of undetermined significance (ASCUS) can be difficult to manage because it is not entirely clear how to follow up or treat such patients. The purpose of this article is to help the physician understand the implication of an abnormal Pap smear, demystify the classification system, and help guide the clinician in choosing rational integrative treatment options for ASCUS and LGSIL, from an integrated medical point of view.

The use of vitamin A, C, E, folic acid, green tea, selenium, carotenes, and indole-3 Carbinol are discussed. This paper also gives the scientific rationale for integrative treatment and prevention strategies, supplies a clinician’s decision tree for the evaluation of the abnormal Pap smear and gives an overview of the various surgical options.

Introduction:

The Papanicolaou test (Pap smear), one of the most effective cancer screening tests available, detects premalignant lesions and has contributed to the decline in cervical cancer morbidity and mortality in the United States since its development in 1941 [1]. Although the Pap smear allows detection of cervical cancer at earlier, more treatable stages, the primary value of the Pap smear is to identify premalignant disease, the treatment of which prevents development of cancers.  The Pap smear detects changes in cellular morphology that are precursors to carcinoma. These morphologic changes, termed cervical intraepithelial neoplasia (CIN), precede the development of cancer by 2 to 15 years. Dysplasia refers to a loss of the normal cytoplasmic differentiation or maturation that occurs with progression from the basal cell to the superficial keratinocyte in the cervical epithelium [2]. The area of development of dysplasia and squamous cell cervical cancers is at the junction of the squamous and columnar epithelia.  The location of this junction, termed the transformation zone, is dynamic and responds to changes in vaginal pH associated with fluctuating estrogen levels [2].

Of the illion Pap smears performed each year in the U.S., 5 to 10 percent are abnormal [2]. The management of patients who have smears categorized as low-grade squamous intraepithelial lesions (LGSIL) or atypical squamous cells of undetermined significance (ASCUS) can be challenging because it is not entirely clear how to follow up with or treat such patients [2]. In contrast, the protocol for high-grade squamous intraepithelial lesions (HGSIL) always involves excision or ablation.  The management of carcinoma in situ and invasive cervical cancer goes beyond the scope of the article and will not be discussed in detail.

The purpose of this article is to help the physician understand the implication of an abnormal Pap smear, demystify the classification system, and help guide the clinician in choosing rational naturopathic treatment options for ASCUS, LGSIL, and HGSIL from an integrated point of view.

Screening

Screening for cervical cancer should start in the late teens or when the patient becomes sexually active [3].  Rates for carcinoma in situ reach a peak for both black and white women between 20 and 30 years of age. For women over 65 with a normal Pap smear, the optimum schedule for repeat testing is not clear [3]. Although vaginal smears are often done for follow-up of women who have had a hysterectomy for malignancy, a retrospective study on routine screening showed no benefit in identifying abnormal cytology for this group [4]. The prevalence of abnormal smears in this group is very low (1.1 %). Over 25% of the total number of invasive cervical cancers occur in women older than 65, and 40% to 50% of all women who die from cervical cancer are over 65 years of age [5].

If the patient is at low risk, Pap smear can be done every three years whereas if the patient is high risk, screening should be done annually. Annual screening may be best, however, because it is easier for patients to remember and keep track of.

Management

Many cases of CIN do not progress. Some spontaneously regress and all have the potential to progress to malignancy (See table 2). The risk for progression from LGSIL to cancer is approximately Ø.15% whereas the risk of high-grade lesions (HGSIL) progressing to cancer is 1.44%[6]

A colposcope is used to evaluate abnormal findings on the cervix.  An endocervical curettage (ECC) is performed to evaluate the cells on the inside of the cervical canal if the cervix stains white after vinegar application. Abnormal areas such as CIN will tend to turn white (acetowhite). The exact reason why CIN tissue turns white with acetic acid is not fully understood. The endocervical curettage does not tear or cut the cervix, but it can be uncomfortable because the procedure causes uterine cramping. A biopsy is necessary to make a diagnosis, however. The decision tree in figure 1 should help the clinician manage the evaluation of abnormal Pap results

Causes and Risk Factors

Increased estrogen stimulation is known to promote cancer in estrogen responsive tissues like the breast, endometrium, larynx, and cervix. Estradiol, a precursor to estrogen, is primarily metabolized to 16 a–hydroxyestrone (16aOHE1) and 2-hydroxyestrone (2OHE) in the body. 16a-hydroxyestrone is strongly estrogenic and exhibits both genotoxic and tumorigenic properties [7], whereas the 2OHE  metabolite has been shown to be weakly anti-estrogenic and antiproliferative [8]. Elevated levels of 16aOHE1, a risk factor for cancer of the breast, endometrium, and cervix, can also increase the expression of HPV 16 [9], a particularly pathogenic viral genotype. Altering these estrogen metabolite ratios to favor 2OHE over 16αOHE1, therefore, becomes a reasonable treatment goal.

Human papillomaviruses (HPV) either alone or in concert with other factors are correlated with 90% of dysplasias and carcinomas [10, 11]. Up to 80 serotypes of HPV have been described (see table 2). Approximately 60% of squamous cell cancer is associated with HPV type 16 [12].  Exposure to HPV generally occurs between the ages of 20 and 40.  Other viruses, which have been implicated in the pathogenesis of cervical dysplasia, are the Herpesvirus and Cytomegalovirus [3]. Dysplasia is most common between the ages of 30 and 40, and cervical cancers are most common between the ages of 50 and 60 [13]. The factors that increase susceptibility to cervical cancer are: [3, 11]

Smoking
Deficiencies of folic acid, vitamins C, E and A
Pregnancy
Immunosupression including HIV infection
Age less than 25 years old (more columnar epithelial cells exposed)
Multiparity
Early age of sexual intercourse
Multiple sexual partners
History of sexually transmitted disease
No prior Pap test
Long term oral contraceptive use
Exposure to radiation
Intrauterine DES exposure
Lupus erythematosus

Classification of Dysplasia:

In 1988, the National Cancer Institute introduced the Bethesda Classification System for Pap smears (see table 3). This system changed the nomenclature for dysplasia. Other systems continue to be used, however, and are often listed in Pap smear reports.
Papanicolaou (Pap)

Classification

Dysplasia
category

CIN

Bethesda system (current)

1 (Benign)

Normal

None

Satisfactory/ WNL

2 (Atypical)

Atypical cells present, some inflammation

None

ASCUS

3 (Suspicious)

Mild to moderate dysplasia

CIN I, CIN II

LGSIL
(HPV or CIN I)

4 (Strongly suspicious)

Severe Dysplasia with carcinoma in situ

CIN III

HGSIL
(includes CIN II and III)

5 (Malignancy)

Invasive

Invasive

Invasive

 

ASCUS = atypical squamous cells of undetermined significance; LGSIL = low-grade squamous intraepithelial lesions; HGSIL = high-grade squamous intraepithelial lesions.

Surgical Treatment Options in the Management of Cervical Dysplasia

Surgery is a valid and often indicated option in the treatment of surgical dysplasia (see table 4). Ablative therapies include cryotherapy  and laser ablation. Excisional therapies include cold knife conization, laser conization, and the loop electroexcision procedure (LEEP). (A complete discussion of each of these techniques is beyond the scope of this paper.) The best care, which extends beyond simply removing the lesion, includes a protocol designed to prevent the recurrence of dysplasia. This can be accomplished through lifestyle and behavior modification, improved diet, nutritional supplementation, and psychological counseling.

Cryotherapy can be performed while in an outpatient setting or at hospital and is best for removing smaller CIN I and II lesions. Liquid nitrogen is used to freeze the tissue, no anesthesia is required, and very little scarring results. Two freezes may be done on the same spot to ensure adequate destruction of abnormal epithelium. A follow-up exam is carried out in 4 months. In addition to recurrence of neoplasia, rare complications include infertility and cervical stenosis [3]. In a ten-year follow up study, Andersen et al. [14]noted an initial cure rate of 91% for CIN II,78% cure rate for CIN III and an overall cure rate of 83.5%. Increasing grade of CIN and endocervical involvement significantly reduced the cure rate. There is no significant influence of age on cure rates. Endocervical involvement should be considered a contraindication to cryotherapy.

Laser ablation is indicated for CIN 1-3 lesions with a diameter larger than 3 cm or which extend up to 5mm into the cervical canal. The beam has a spot size of1 mm in diameter and has a depth of 5 to 7 mm.  Complications are pain and bleeding. Healing is usually complete in four to six weeks. In a ten-year follow-up study Baggish et al. [15]noted a 94% cure rate after one year.

LEEP involves using an electrosurgical unit with both cutting and coagulation capabilities. Different sized electrodes with a wire loop at the end are used to excise tissue (after colposcopy is completed). The cervix is injected with a local anesthetic and vasopressin  [3]. The electrode is then passed across the cervix, excising the transformation zone and producing a pathologic specimen. The advantage to the LEEP is that not only does it treat, but it also confirms the diagnosis and makes sure that the borders are free of CIN.

Conization is performed if the colposcopy is unsatisfactory, if invasive disease is suspected, or there is an endocervical neoplasm.Conization is also an option for patients that prefer a less invasive procedure than hysterectomy. Conization is preferable to LEEP for the evaluation of adenocarcinoma in situ. This procedure is performed in the hospital under general anesthetia and involves using a laser or scalpel (cold knife cone) to make a cone-shaped excision into the exocervix or endocervix. The sample of tissue is examined under a microscope for any signs of cancer. This biopsy may serve as the treatment, as well, if all of the diseased tissue is removed.

Long-term complications of excisional therapies include: cervical stenosis, infertility, loss of cervical mucus, and an increase in preterm births.  A definitive conclusion is not yet available on the degree of risks from conization although at least one study demonstrated high risk of preterm delivery [16].
Ahlgren et al. [17]noted a cure rate of 98% if the margin of the conization was free of CIN, whereas the rate fell to only 70 % for patients positive for CIN at the margin. The follow-up period ranged from 1 to 5 years.
Treatment Method

Indications

Advantages

Disadvantages

Cryotherapy

Cost of the procedure: $255.00 (outpatient)*

CIN 1-2 [13]; Small lesion; Ectocervical location; Negative ECC; No endocervical gland involvement

Reliability;
Ease of use;
Low cost

Inability to tailor to lesion size; No pathologic specimen

Laser ablation

Cost of the procedure: $305.00
(outpatient)

CIN 1-3 [13];
Large lesions;
Irregular cervix;
Vaginal extension of dysplasia;
Satellite lesions

Reliability;
Can be tailored to lesion size;
Rapid healing

Expensive equipment/training;
Complications (eye injury, burns);
No pathologic specimen

LEEP

Cost of the procedure: $355.00
(outpatient)

CIN 1-3[13];
Unsatisfactory colposcopy;
Positive ECC;
Significant discrepancy between cytology and histology;
Suspicion of invasion
Glandular dysplasia

Reliability;
Ease of use;
Can be tailored to lesion size;
Produces pathologic specimen; office procedure

Higher cost
May increase risk of preterm delivery, infertility, or cause cervical stenosis

Conization

Cost of the procedure: $1,200
(inpatient)

CIN III and invasive;
colposcopy is unsatisfactory; invasive disease is suspected; endocervical neoplasm

Produces pathologic specimen, may be as effective as hysterectomy for carcinoma in situ, preserves fertility

May increase risk of preterm delivery, infertility, or cause cervical stenosis; expensive; requires anesthesia

CIN = cervical intraepithelial neoplasia; ECC = endocervical curettage; LEEP = loop electrosurgical excision procedure.
* Based on average costs in Seattle, and determined by calling three of the main centers for gynecologic care.

Nutritional and Herbal Therapies: ASCUS and LSIL (CIN1, CIN 2)

Topical treatments

Vitamin A: A vitamin A palmitate suppository is the preferred delivery form of vitamin A.. Topically applied vitamin A has been used successfully in patients with CIN 1-2 but not CIN 3 [18, 19].
Escharotic treatment: This in-office procedure is indicated for condyloma with CIN 1, CIN 2, and CIN3 (low-risk patient). The ten-step procedure includes painting the cervix with Bromelain (a proteoloytic enzyme), Calendula succus (the juice pressed out of the fresh flowers of Calendula), a tincture of Sanguinaria (bloodroot), and inserting a “Vag Pack.” The Vag Pack (anhydrous magnesium sulfate, Glycerin, Hydrastis (Goldenseal), Thuja oil (Red cedar), Tea tree oil, Bitter orange oil, 500,000 IU of Vitamin A palmitate, Iron sulfate) is essentially an antiviral, antifungal, and antibacterial Vitamin A delivery system used by naturopathic physicians for a variety of vaginal complaints. [20]. The patient receives two treatments over a five-week period. This option is most indicated for those patients who refuse conventional treatment. The main benefits are less scarring to the cervix, fewer surgical complications and psychological benefits to the patient, which include less fear and anxiety, because it can be performed in an outpatient setting by a family physician. Additionally, this self-selected “natural approach” may coincide more closely with the patient’s worldview.  To date, the clinical efficacy of this procedure has not been scientifically studied.

Systemic treatments:

Folic acid: Low folate status is associated with cervical dysplasia and may enhance the effect of other risk factors for cervical dysplasia, specifically HPV-16 infection [21]. Oral contraceptives reduce folate storage in the body and result in megaloblastic changes on the cervix and can be reversed with folic acid [22]. Several studies have demonstrated that high dose folate can cause normalization of Pap smears and biopsies [23-25], although several more recent studies do not support this notion [26-28]. It has been demonstrated that DNA hypomethylation is significantly associated with the grade of CIN [29]. Serum folate, however, has not been shown to correlate well with methylation or cervical folate levels. Thus, the concept that serum folate level is significantly related to DNA hypomethylation remains to be proven [29]. This non-toxic treatment is especially indicated in patients on oral contraceptives. The effective dose is 5-10 mg/day for 3-6 months [23-25]. Reports of side effects are very rare. Caution should be used in patients with undiagnosed anemia. Folate may affect the therapeutic activity of some anticonvulsant drugs [30]. Other drugs may either decrease absorption of folate or have a beneficial interaction with folate.  Because doses above 1 mg may exacerbate (or mask) the neurological damage of vitamin B12 deficiency [30],  B12 (400-1,000 mcg) should also be administered as a precaution [31].

Mixed carotenoids: Although no clinical trials have tested mixed carotenoids for the treatment of CIN, it is well established that deficiency in one or more of these plant pigments is associated with increased risk of CIN [32-35].  Low intake of β-carotene is associated with an increased risk of cervical dysplasia [36]. Also, low serum levels of β-carotene are associated with increased risk of cervical cancer [36]. Randomized trials using β-carotene have provided mixed results; some have even demonstrated increased progression to squamous atypia [36]; therefore, this nutrient should be administered as it is found in nature, with other carotenoids. Lycopene may be of particular importance because research suggests that elevated levels of serum lycopene may offer some protection against cervical dysplasia. [34]. Regression of cervical lesions with β-carotene has been achieved in women with pretreatment low serum retinol levels [36]suggesting that a subgroup of women with low vitamin A and β-carotene intake may benefit the most from chemoprevention with carotenes.

Vitamin E succinate: The vitamin E analog alpha-tocopheryl succinate can induce apoptosis (cell death) in cancer cell lines, although human intervention trials have not yet been conducted [37-39].  In mice with colon cancer, vitamin E succinate suppressed tumor growth by 80% [38, 39]. This degree of tumor suppression strongly supports the use of this non-toxic compound in the treatment and prevention of cervical cancer. Evidence for the role of other forms of vitamin E
in cancer prevention and treatment are mixed. The best evidence to date exists for the succinate form. Vitamin E succinate stimulates the death of tumor cells in two ways: by increasing the activation of TGF- ß, and by increasing this growth factor’s ability to deliver its apoptotic signal [37-39]. It is worth noting that Vitamin E can also decrease platelet aggregation. Thus, in patients undergoing a surgical procedure, stopping vitamin E for one month before, and during, surgery would be prudent.

Vitamin C: There is a known association between low vitamin C status and incidence of cervical dysplasia [40-42]. Evidence also suggests that vitamin C from food may provide a protective effect in colon, esophageal, laryngeal, bladder, cervical, rectal, breast, and perhaps lung cancer [43].  Vitamin C and beta-carotene were tested on 141 women with ASCUS or CIN I over 2 years of follow-up, at daily doses of 500 mg and 30 mg, respectively [44].  A statistically significant rate of regression was not achieved with this low-dose regimen. Just as with beta-carotene, it may be that the natural dietary substances that come along with vitamin C (bioflavanoids such as rutin, quercetin, kaempferol, naringenin, hesperitin, etc)  play a more important role in cancer prevention than the vitamin alone. The minimal cost and low toxicity coupled with its role in primary cancer prevention provide the rationale for its use. Because intervention studies with vitamin C are lacking, further research is warranted.

Selenium: Extensive data support the notion that selenium intake is inversely correlated with cancer incidence and cancer deaths rise when dietary intake of selenium is low (below 50 mcg) [45].  In one pivotal trial originally designed to look at skin cancer, 1,312 individuals were divided into two groups. One group received 200 mcg of selenium daily; the other received placebo. Participants were not deficient in selenium. The researchers saw such dramatic declines in the incidence of several other cancers in the selenium group, that for ethical reasons, they felt compelled to allow all participants to take selenium. A number of Chinese studies also indicate that giving selenium to people who live in selenium-deficient areas reduces the incidence of cancer [47]. One study examined whether selenium could reduce cancer metastasis in mice. A modest dosage of selenium reduced metastasis by 57% [48]. Another recent animal study examined whether two experimental organic forms of selenium would protect rats against experimentally induced cancer of the tongue [49].  None of the rats in the selenium group developed tumors compared to 47% tumor development in the placebo group.

Green tea: The active ingredients in green tea are believed to be the polyphenols, especially epigallocatechin gallate (EGCG). These antioxidant polyphenols may block the formation of nitrosamines and other cancer-causing compounds and help detoxify carcinogens [50].  Studies suggest that EGCG may help prevent skin cancer if it is applied directly to epithelial tissue [51]and exerts an estrogen-blocking effect that is helpful in preventing breast and uterine cancer [52]. In vitro and animal studies suggest that green tea consumption protects against cancers of the stomach, lung, liver esophagus, pancreas, breast, duodenum, and colon [53]. A skin cancer study found that green tea inhibited skin cancer in mice exposed to ultraviolet light and other carcinogens [54]. After 8 months, animals ingesting green tea at human intake levels had 72 to 93% fewer skin tumors than the placebo group. The reasonable cost, low toxicity, and strong evidence from animal intervention trials, may support the role of green tea in secondary cancer prevention.

Indole-3 Carbinol (I3C) has been shown to shift metabolism of estradiol from the 16aOHE1 to the 2OHE metabolite of estradiol [55, 56]. As mentioned previously the 16αOHE1 metabolite of estrogen is implicated in causing cancer whereas the 2OHE version is weakly anti-estrogenic and may protect against the development of cancer. Thus, I3C may offer a protective effect by lowering estrogenic stimulation. Other proposed explanations for the effectiveness of I3C include partially inactivating estrogen [56, 57], inhibiting tumor cell replication [58], and fighting free radicals [59].  I3C increases 2-hydroxylation of estrogens via induction of cytochrome P450 (CYP1A1). I3C must be exposed to stomach acid, where it is converted to diindolymethane (DIM) and carbazole, to exert its full effects [60].

A 12-week placebo-controlled trial of 30 women with LGSIL or HGSIL found that treatment with I3C (200 or 400 mg/day significantly improved the rate of regression of CIN [61].
I3C is safe at recommended doses [62]and human studies have found no significant side effects [61, 63, 64].  Most studies report inhibitory or protective effects of I3C, although a few animal studies have demonstrated promotion or enhancement of cancer activity, depending upon the substance used, experiment protocol and animal species [65, 66]. More research on humans should be conducted before I3C is used indiscriminately. I3C is found in cruciferous vegetables such as cabbage, broccoli, Brussels sprouts, cauliflower, kale, kohlrabi, and turnips. A typical Japanese diet provides the equivalent of about 112 mg of I3C daily; intake in Western diets is lower [58, 61].

See Table 5 for a summary and dosages.

Table 5: Summary of Treatment Options

Dysplasia grade

Therapy

Dose

Research support

Adverse reactions, contraindications and precautions (respectively)

ASCUS, LGSIL

Vitamin A palmitate

Suppository (500,000 IU), nightly for two alternating weeks [18, 19]

Human, in vivo

Pregnancy; hypersensitivity to vitamin A

 

Escharotics

Topical, twice a week for 4-5 weeks [20]

Traditional naturopathic use, empirical data

Tissue irritation; HGSIL, “high risk” or non-compliant patient

 

Folic acid

5-10 mg/ day for 3-6 months [23-25]

Human, in vivo

Adverse reactions very rare; undiagnosed anemia, give with B12 to avoid complications

 

Mixed natural carotenes

150,000 IU/ day (no clinical trials have tested mixed carotenoids for the treatment of CIN)

Epidemiological association with dysplasia

Carotenodermia (yellowish discoloration of the skin); Supplemental beta carotene greater than 20 mg/ day is associated with lung cancer in smokers

 

Vitamin C

6000 mg/ day
(extrapolation from epidemiological studies)
Epidemiological association with dysplasia/ primary cancer prevention

Intake of over 3 g/ day may cause nausea, abdominal distention, cramps and diarrhea; no contraindications other than hypersensitivity, renal disease of preexisting kidney stone disease (serum creatinine less than 30), pregnancy.

 

Selenium

200 mcg/ day
[46]

Epidemiological association with prevention of cancer

No adverse reactions at doses less than 900 mg; hypersensitivity; pregnancy

 

Vitamin E succinate

350 mg/ day
[37-39]

Human (in vitro)
Animal (in vivo)

No adverse reaction at doses less than 1000 mg; hypersensitivity;  those on warfarin should have their INR monitored, vitamin K deficiency, pregnancy and nursing mothers, surgery (stop one month prior to surgery)

 

Green tea

900 mg of standardized extract or 6-10 cups/ day [53]

Epidemiological association with cancer prevention and animal studies (in vitro and in vivo)

No known adverse reactions; hypersensitivity; pregnancy and nursing, anticoagulants and bleeding disorders

 

Indole-3 Carbinol

200-800 mg/ day (It is difficult to get this dose from diet alone ) [61, 63, 64]

Extrapolation from estrogen metabolism studies/ one human intervention trial

No adverse reactions; hypersensitivity; pregnancy and nursing

HGSIL or LGSIL (high risk patient)

All the above treatments can be used as adjunct to surgery

Prevention of Cervical Dysplasia:

As mentioned previously, nutritional deficiencies are associated with incidence of cervical dysplasia. One study showed that up to 67% of those with cervical dysplasia had nutritional deficiencies [67].  Nutrient deficiencies commonly associated with cervical dysplasia include beta-carotene, vitamin C, vitamin B6, selenium, and folate [68, 69].
According to available data, soy, which contains isoflavones, , may help prevent hormone-related cancers such as prostate, breast, and uterine cancer [70].Toxicology studies have found soy isoflavones to be basically safe. However, due to considerable contradictory evidence and the potential role of isoflavones in promoting breast cancer in animals [71, 72], soy use should be based on patient risk and physician discretion. One very preliminary study on humans found evidence of increased breast cancer risk with use a soy protein product [73].

A prevention checklist includes:

Using condoms to prevent exposure to HPV
Reducing sexual risk factors (multiple partners, early intercourse)
Receiving an annual Pap smear (early detection and preventing progression)
Eating a whole foods, organically grown, low saturated fat diet high in fruits and vegetables (phytonutrients, omega-3 fatty acids, and fiber all reduce cancer risk)
Avoidance of smoking

Summary:
After three or more consecutive normal examinations, the Pap test may be performed less frequently in low-risk women (up to every 3 years) at the discretion of the clinician. Women with one or more risk factors for cervical cancer should be screened annually. If a satisfactory colposcopic examination with biopsy has confirmed the presence of HGSIL, excision or ablative therapy is always indicated. Treatment is also indicated for those patients with histologically confirmed LGSIL that has been persistent for more than 6 months.The link between high levels of 16a-OHE1 (bad) and low 2-OHE1 (good) in women with CIN, and the association between chronic estrogen exposure and HPV16, provides a basis for modulating estrogen metabolism for the prevention and treatment of CIN. Prevention is a fundamental pillar of naturopathic and integrative medicine. Integrative and natural medicine protocols are indicated for primary treatment and prevention of ASCUS, LGSIL and for adjunctive treatment of HGSIL. The primary goal of treatment is to improve the chances that a lesion will regress, reassure the patient, and decrease the rate of recurrence.  Continued research is needed to more clearly ascertain the effectiveness of nutritional and botanical approaches in the treatment of cervical dysplasia and cervical cancer.

References:

1.         Results from the National Breast and Cervical Cancer Early Detection Program, October 31, 1991-September 30, 1993. MMWR Morb Mortal Wkly Rep 1994;43:530-534.
2.         Korn A, Innovations in Pap Screening for Cervical Neoplasia. Medscape Women’s Health,http://www.medscape.com/Medscape/WomensHealth/journal/1996/v01.n10/w155.korn/w155.korn.html 1996; Accessed 01/2001.
3.         Mishell D R, Comprehensive gynecology.3rd ed. St. Louis: Mosby; 1997:x, 1281.
4.         Pearce K F, Haefner H K, Sarwar S F, et al., Cytopathological findings on vaginal Papanicolaou smears after hysterectomy for benign gynecologic disease. N Engl J Med 1996;335:1559-1562.
5.         Remington P, Lantz P, and Phillips J L, Cervical cancer deaths among older women: implications for prevention. Wis Med J 1990;89:30, 32-34.
6.         Melnikow J, Nuovo J, Willan A R, et al., Natural history of cervical squamous intraepithelial lesions: a meta- analysis. Obstet Gynecol 1998;92:727-735.
7.         Telang N T, Suto A, Wong G Y, et al., Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst 1992;84:634-638.
8.         Schneider J, Huh M M, Bradlow H L, et al., Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem 1984;259:4840-4845.
9.         Mitrani-Rosenbaum S, Tsvieli R, and Tur-Kaspa R, Oestrogen stimulates differential transcription of human papillomavirus type 16 in SiHa cervical carcinoma cells. J Gen Virol 1989;70:2227-2232.
10.       Wright T C, Jr. and Richart R M, Role of human papillomavirus in the pathogenesis of genital tract warts and cancer. Gynecol Oncol 1990;37:151-164.
11.       Syrjanen K J, Spontaneous evolution of intraepithelial lesions according to the grade and type of the implicated human papillomavirus (HPV). Eur J Obstet Gynecol Reprod Biol 1996;65:45-53.
12.       Chang D Y, Chen R J, Lee S C, et al., Prevalence of single and multiple infection with human papillomaviruses in various grades of cervical neoplasia. J Med Microbiol 1997;46:54-60.
13.       Bristow R E and Montz F J, Workup of the abnormal Pap test [In Process Citation]. Clin Cornerstone 2000;3:12-24.
14.       Andersen E S and Husth M, Cryosurgery for cervical intraepithelial neoplasia: 10-year follow-up. Gynecol Oncol 1992;45:240-242.
15.       Baggish M S, Dorsey J H, and Adelson M, A ten-year experience treating cervical intraepithelial neoplasia with the CO2 laser. Am J Obstet Gynecol 1989;161:60-68.
16.       Kristensen J, Langhoff-Roos J, and Kristensen F B, Increased risk of preterm birth in women with cervical conization. Obstet Gynecol 1993;81:1005-1008.
17.       Ahlgren M, Ingemarsson I, Lindberg L G, et al., Conization as treatment of carcinoma in situ of the uterine cervix. Obstet Gynecol 1975;46:135-139.
18.       Meyskens F L, Jr., Surwit E, Moon T E, et al., Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J Natl Canc Inst 1994;86:539-543.
19.       Graham V, Surwit E S, Weiner S, et al., Phase II trial of beta-all-trans-retinoic acid for cervical intraepithelial neoplasia delivered via a collagen sponge and cervical cap. West J Med 1986;145:192-195.
20.       Hudson T, Women’s Encyclopedia of Natural Medicine.1st ed. Los Angeles, CA: Keats; 1999:.
21.       Butterworth C E, Jr., Hatch K D, Macaluso M, et al., Folate deficiency and cervical dysplasia. Jama 1992;267:528-533.
22.       Li X, Ran J, and Rao H, [Megaloblastic changes in cervical epithelium associated with oral contraceptives and changes after treatment with folic acid]. Zhonghua Fu Chan Ke Za Zhi 1995;30:410-413.
23.       Streiff R R, Folate deficiency and oral contraceptives. Jama 1970;214:105-108.
24.       Whitehead N, Reyner F, and Lindenbaum J, Megaloblastic changes in the cervical epithelium. Association with oral contraceptive therapy and reversal with folic acid. Jama 1973;226:1421-1424.
25.       Butterworth C E, Jr., Hatch K D, Gore H, et al., Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982;35:73-82.
26.       Butterworth C E, Jr., Hatch K D, Soong S J, et al., Oral folic acid supplementation for cervical dysplasia: a clinical intervention trial. Am J Obstet Gynecol 1992;166:803-809.
27.       Childers J M, Chu J, Voigt L F, et al., Chemoprevention of cervical cancer with folic acid: a phase III Southwest Oncology Group Intergroup study. Cancer Epidemiol Biomarkers Prev 1995;4:155-159.
28.       Zarcone R, Bellini P, Carfora E, et al., [Folic acid and cervix dysplasia]. Minerva Ginecol 1996;48:397-400.
29.       Fowler B M, Giuliano A R, Piyathilake C, et al., Hypomethylation in cervical tissue: is there a correlation with folate status? Cancer Epidemiol Biomarkers Prev 1998;7:901-906.
30.       Hendler S and Rorvik D, eds.PDR for Nutritional Supplements. Vol. 1.  Montvale, NJ: Medical Economics Company, Inc.; 2001:.
31.       Murray M, Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima; 1996:.
32.       VanEenwyk J, Davis F G, and Bowen P E, Dietary and serum carotenoids and cervical intraepithelial neoplasia. Int J Cancer 1991;48:34-38.
33.       Nagata C, Shimizu H, Yoshikawa H, et al., Serum carotenoids and vitamins and risk of cervical dysplasia from a case-control study in Japan. Br J Cancer 1999;81:1234-1237.
34.       Kantesky P A, Gammon M D, Mandelblatt J, et al., Dietary intake and blood levels of lycopene: association with cervical dysplasia among non-Hispanic, black women. Nutr Cancer 1998;31:31-40.
35.       de Vet H C, Knipschild P G, Grol M E, et al., The role of beta-carotene and other dietary factors in the aetiology of cervical dysplasia: results of a case-control study. Int J Epidemiol 1991;20:603-610.
36.       Keefe K A, Schell M J, Brewer C, et al., A randomized, double blind, Phase III trial using oral beta-carotene supplementation for women with high-grade cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 2001;10:1029-1035.
37.       Rose A T and McFadden D W, Alpha-tocopherol succinate inhibits growth of gastric cancer cells in vitro. J Surg Res 2001;95:19-22.
38.       Neuzil J, Weber T, Gellert N, et al., Selective cancer cell killing by alpha-tocopheryl succinate. Br J Cancer 2001;84:87-89.
39.       Neuzil J, Weber T, Schroder A, et al., Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements. Faseb J 2001;15:403-415.
40.       Basu J, Palan P R, Vermund S H, et al., Plasma ascorbic acid and beta-carotene levels in women evaluated for HPV infection, smoking, and cervix dysplasia. Cancer Detect Prev 1991;15:165-170.
41.       Wassertheil-Smoller S, Romney S L, Wylie-Rosett J, et al., Dietary vitamin C and uterine cervical dysplasia. Am J Epidemiol 1981;114:714-724.
42.       Romney S L, Duttagupta C, Basu J, et al., Plasma vitamin C and uterine cervical dysplasia. Am J Obstet Gynecol 1985;151:976-980.
43.       Flagg E W, Coates R J, and Greenberg R S, Epidemiologic studies of antioxidants and cancer in humans. J Am Coll Nutr 1995;14:419-427.
44.       Mackerras D, Irwig L, Simpson J M, et al., Randomized double-blind trial of beta-carotene and vitamin C in women with minor cervical abnormalities. Br J Cancer 1999;79:1448-1453.
45.       Hocman G, Chemoprevention of cancer: selenium. Int J Biochem 1988;20:123-132.
46.       Clark L C, Combs G F, Jr., Turnbull B W, et al., Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. Jama 1996;276:1957-1963.
47.       Yu S Y, Zhu Y J, and Li W G, Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res 1997;56:117-124.
48.       Yan L, Yee J A, McGuire M H, et al., Effect of dietary supplementation of selenite on pulmonary metastasis of melanoma cells in mice. Nutr Cancer 1997;28:165-169.
49.       Tanaka T, Makita H, Kawabata K, et al., 1,4-phenylenebis(methylene)selenocyanate exerts exceptional chemopreventive activity in rat tongue carcinogenesis. Cancer Res 1997;57:3644-3648.
50.       Stich H F, Teas and tea components as inhibitors of carcinogen formation in model systems and man. Prev Med 1992;21:377-384.
51.       Katiyar S K, Ahmad N, and Mukhtar H, Green tea and skin. Arch Dermatol 2000;136:989-994.
52.       Imai K, Suga K, and Nakachi K, Cancer-preventive effects of drinking green tea among a Japanese population. Prev Med 1997;26:769-775.
53.       Katiyar S K and Mukhtar H, Tea antioxidants in cancer chemoprevention. J Cell Biochem Suppl 1997;27:59-67.
54.       Wang Z Y, Huang M T, Lou Y R, et al., Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induced skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated SKH-1 mice. Cancer Res 1994;54:3428-3435.
55.       Michnovicz J J, Adlercreutz H, and Bradlow H L, Changes in levels of urinary estrogen metabolites after oral indole-3- carbinol treatment in humans. J Natl Cancer Inst 1997;89:718-723.
56.       Yuan F, Chen D Z, Liu K, et al., Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res 1999;19:1673-1680.
57.       Michnovicz J J, Increased estrogen 2-hydroxylation in obese women using oral indole-3- carbinol. Int J Obes Relat Metab Disord 1998;22:227-229.
58.       Bradlow H L, Sepkovic D W, Telang N T, et al., Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent. Ann N Y Acad Sci 1999;889:204-213.
59.       Arnao M B, Sanchez-Bravo J, and Acosta M, Indole-3-carbinol as a scavenger of free radicals. Biochem Mol Biol Int 1996;39:1125-1134.
60.       Bradfield C A and Bjeldanes L F, Modification of carcinogen metabolism by indolylic autolysis products of Brassica oleraceae. Adv Exp Med Biol 1991;289:153-163.
61.       Bell M C, Crowley-Nowick P, Bradlow H L, et al., Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol 2000;78:123-129.
62.       Background information. Indole-3-carbinol (I3C). 700-06-1 J, 2000. National Institute of Environmental Health Sciences web site. Available at: http://ntp-server.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/Indolecarbinol.html. Accessed September 7, 2001, .
63.       Wong G Y, Bradlow L, Sepkovic D, et al., Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl 1997;29:111-116.
64.       Rosen C A, Woodson G E, Thompson J W, et al., Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg 1998;118:810-815.
65.       Dashwood R H, Indole-3-carbinol: anticarcinogen or tumor promoter in brassica vegetables? Chem Biol Interact 1998;110:1-5.
66.       Bailey G S, Hendricks J D, Shelton D W, et al., Enhancement of carcinogenesis by the natural anticarcinogen indole-3- carbinol. J Natl Cancer Inst 1987;78:931-934.
67.       Orr J W, Jr., Wilson K, Bodiford C, et al., Nutritional status of patients with untreated cervical cancer. I. Biochemical and immunologic assessment. Am J Obstet Gynecol 1985;151:625-631.
68.       Romney S L, Palan P R, Basu J, et al., Nutrient antioxidants in the pathogenesis and prevention of cervical dysplasias and cancer. J Cell Biochem Suppl 1995;23:96-103.
69.       Butterworth C E, Jr., Effect of folate on cervical cancer. Synergism among risk factors. Ann N Y Acad Sci 1992;669:293-299.
70.       Adlercreutz H and Mazur W, Phyto-oestrogens and Western diseases. Ann Med 1997;29:95-120.
71.       Allred C D, Allred K F, Ju Y H, et al., Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. Cancer Res 2001;61:5045-5050.
72.       Ju Y H, Allred C D, Allred K F, et al., Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. J Nutr 2001;131:2957-2962.
73.       Petrakis N L, Barnes S, King E B, et al., Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. Cancer Epidemiol Biomarkers Prev 1996;5:785-794.