In 1999, about 4,800 women died from cervical cancer in the U.S.1. In addition cervical cancer is the second most prevalent cancer of women in developing countries2.
Yes. Rhesus monkeys that were given high doses of medroxyprogesterone (Depo-Provera®) developed cervical cancer3. In addition, animal cells have turned cancerous in the presence of the human papilloma virus (HPV) and norgestrel, a common type of progestin found in many of today's oral contraceptives4. Last, norethynodrel, another artificial progestin found in today's OCPs, caused cervical cancer in mice5.
Yes, there are many studies that link OCP use to an increased risk of cervical carcinoma but before proceeding further it should be noted that there are three main types of invasive cervical cancer. Squamos cervical cancer comprises about 90% of all types, and adenosquamos and adenocarcinoma make up the remaining 10%6.
In 1992, Delgado-Rodriguez7 published a metaanalysis which showed that "ever" versus "never" use of OCPs resulted in a 21% increased risk [RR=1.21 (1.1-1.4)] for invasive cervical cancer and a 1.52-fold risk (1.3-1.8) for carcinoma in situ (de, the preliminary stage of cervical cancer). Unfortunately, much of their data came from studies which took their information before the 1980s. Because women were taking OCPs for far shorter periods of time in the 1960s and 1970s than in the 1980s and 1990s, and because these earlier studies did not have an adequate latent period, the inclusion of the earlier studies in the metaanalysis results in an underestimate of the relative risk.
In 1993, the most massive worldwide study8 known to date (conducted by the World Health Organization) was published which examined the risk of OCP use and invasive squamos cervical carcinoma (de, the most prominent type). It examined more than 2,300 women who had cervical carcinoma and noted some critical results: 1) if a woman had ever taken an OCP her risk of invasive cervical carcinoma increased by 31% (statistically sign)ficant at the 95% confidence level); 2) women who took OCPs for over 5 years had a 51% increased risk [RR= 1.51 (1.22-1.86)] and those who took them for over 8 years had a 123% increased risk [RR= 2.23 (1.84-2.70)]; 3) women who had taken OCPs before the age of 25 had a 45% increased risk [RR=1.45 (1.24-1.70)]; and 4) women who first started using OCPs as long as 15 years ago had a 37% increased risk of developing cervical carcinoma [RR=1.37 (1.19-1.57)].
Tables 13A, 13B, 13C, and 13D give the reader an idea of just how strong the link between OCP use and invasive cervical cancer is. The calculations for the weighted average risks are given at the end of the chapter and allow us to estimate a crude estimate for the relative risk for each of the tables. Table 13A yields an elevated risk of 29.66% for cervical cancer if a woman ever used OCPs. Table 13B yields a risk of 61.97% for long-term use of 5 to 10 years of use or more. In Table 13C one sees that OCP use before the age of 20 increases the risk of developing invasive cervical cancer by 80.01%, whereas Table 13D shows that use before age 25 yields a 64.51% increased risk.
| Table 13A: | ||||
|---|---|---|---|---|
| Ener vs. Never Use of Oral Contraceptives and Risk for Invasive Cervical Cancer | ||||
| Author | Percent Change | Years Studied | Patients in Category | Results |
| Beral et al9 | 80% increase* | 1987 | 49 | 1.8 (1,0-3.3) |
| Brinton et al10 | 21% increase* | 1986-1987 | 759 Latin-American women | 1.21 (0.9-1.6) |
| Brinton et al11 | 49% increase | 1982-1984 | 479: stack effect | 1.49 (1.1-2.1) |
| Celentano et al12 | 52% (decrease) | 1982-1984 | 85 less than age 45 | 0.48 (0.22-0.95) |
| Daling et al13 | no change | 1986-1992 | 221 | 1.0 (0.6-1.6) |
| Ebeling et al14 | 51% increase* | 1983-1985 | 129 | 1.51 (0.78-2.92) |
| Irwin et al15 | 20% (decrease)* | 1982-1984 | 149: stack effect | 0.8 (0.5-1.3) |
| Kjaer et al16 | 30% increase* | 1987-1988 | 58: stack effect | 1.3 (0.5-3.3) |
| Parrazini et al17 | no change* | 1981-1993 | 257: stock effect | 1.0 (0.7-1.6) |
| Peters et al18 | no change | 1980-0981 | 198 | 1.0 (no CTs given) |
| Thomas et al19 WHOs | 50% increase | 1979-1988 | 376 | 1.5 (1.1-1.9) |
| Thomas et al (8) | 31% increase | 1979-1988 | 2,361 | 1.31 (1.19-1.45) |
| Ursin et al20 | 110% increase | 1977-1991 | 195 | 2.1 (1.1-3.8) |
| *This result reflects a trend toward an increased or decreased risk but does not attain statistical significance. | ||||
| Table 13B: | ||||
|---|---|---|---|---|
| Long-Term Use of Oral Contraceptives and Risk for Invasive Cervical Cancer | ||||
| Author | Percent Change | Years Studied | Patients in Category | Results |
| Brinton et al (10) | 37% increase* | 1986-1987 | 759 non-U.S. women |
1.37 (0.9-2.0)
for 5-9 years use |
| Brinton et al (11) | 82% increase | 1982-1984 | 479: stack effect |
1.82 (1.1-3.1)
for >5 years use |
| Daling et al (13) | 30% increase* | 1986-1992 | 221 |
1.3 (0.7-2.2)
for >5 years use |
| Ebeling et al (14) | 76% increase* | 1983-1985 | 129 |
1.76 (0.95-8.92)
for >7 years use |
| Irwin et al (15) | 10% (decrease)* | 1982-1984 | 149: stack effect |
0.9 (0.5-1.6)
for >5 years use |
| Kjaer et al (16) | 30% increase* | 1987-1988 | 56: stack effect |
1.3 (0.5-3.5)
for > or = 6 years use |
| Parrazini et al21 | 147% increase | 1981-1987 | 367: stock effect |
1.0 (0.7-1.6)
for >2 years use |
| Thomas et al (19) WHO | 120% increase | 1979-1988 | 376 |
2.2 (1.4-3.5)
for >8 years use |
| Thomas et al (8) | 51% increase | 1979-1988 | 2,361 |
1.51 (1.22-1.86)
for more than 5 years use |
| Ursin et al (20) | 340% increase | 1977-1991 | 195 |
4.4 (1.8-10.8)
for >12 years use |
| Table 13C: | ||||
|---|---|---|---|---|
| Use of OCPs Before the Age of 20 and Risk for Invasive Cervical Cancer | ||||
| Author | Percent Change | Years Studied | Patients in Category | Results |
| Brinton et al (10) | 46% increase* | 1986-1987 | 759 Latin-American women |
1.46 (0.8-2.6)
before age 20 |
| Brinton et al (11) | 28% increase* | 1982-1984 | 479: stack effect |
1.28 (0.8-2.1)
before age 20 |
| Daling et al (13) | 130% increase* | 1986-1992 | 221 |
2.3 (1.4-3.8)
before age 18 |
| Kjaer et al (16) | 30% increase* | 1987-1988 | 56: stack effect |
1.3? (0.5-3.5)
before age 20 |
| Thomas et al (19) | 230% increase | 1979-1988 | 376 |
3.3 (1.7-6.6)
before age 20 |
| Ursin et al (20) | 10% increase* | 1977-1991 | 195 |
1.1 (0.3-3.3)
before age 17 |
| Table 13D: | ||||
|---|---|---|---|---|
| Risks For Women Who Used OCPS Before the Age of 25 | ||||
| Author | Percent Change | Years Studied | Number of Patients | Results |
| Ebeling et al (14) | 204% increase | 1983-1985 | 129 |
3.04 (1.14-8.13)
before age 25 |
| Parrazini et al (21) | 141% increase* | 1981-1987 | 367: stock effect |
2.41 (0.98-5.93)
before age 25 |
| Thomas et al (8) | 45% increase | 1979-1988 | 2,361 |
1.45 (1.24-1.70)
before age 25 |
| *This result reflects a trend toward an increased or decreased risk but does not attain statistical significance. | ||||
Perhaps the most alarming statistic is the one based on the data from Table 13C. If women who use OCPs before the age of 20 truly end up having a long-term increased risk of cervical cancer of over 80%, then these women ought to be made aware of their increased risk and receive frequent Pap smears. A meta-analysis in this area is desperately needed.
Yes. Herrero et al22, in a large study, found that women who had received injectable progestins (de, usually DMPA [depot-medroxyprogesterone] or norethisterone enanthate) for at least 5 years and who had used them at least 5 years ago suffered a 430% increased risk of developing cervical cancer [RR=5.3 (1.1-10.0)].
Brinton et al [10] in their fairly large study of 759 women who had cervical cancer noted that OCP use increased the risk for cervical cancer although the study controlled for the variable of HPV status. In addition, the authors of the large WHO study [8] believed that HPV and OCP use were not confounding variables because they found no evidence of confounding in those variables closely related to HPV such as anal or genital warts. It would probably be wise to perform more studies which specifically control for HPV status in the future. Until more studies are performed, it would appear that both HPV status and OCP use are real factors in elevating a woman's risk for invasive cervical carcinoma. One animal study [4] and one human study23 have suggested that OCPs actually accelerate or enhance the process of cervical carcinogenesis in the woman who is already infected with HPV.
Let us take the information provided in the first section of Table 13C. We note below that it provides us with the risk of cervical cancer for women who had taken OCPs before age 20. The second column (A) shows how much a particular study increased the risk of cervical cancer, whereas the third column (B) shows how many patients were involved in the study. In order to estimate what the total effect of OCP use before the age of 20 is, as concerns the risk of cervical cancer, one must estimate the risk of each individual study and sum up their risks. To do this, one must factor in two parameters for each study. The first is the percentage change that a study showed (column A) and the second is the size of the study (column B). Multiplying these two parameters (A x B) yields the "weighted contribution" of increase for each study. Totaling each of the weighted contributions yields a total of 1671.68. If one now divides this number by the total number of patients (de, the sum of column C, or 2086) one obtains an estimate for the effect of OCP use on the risk of cervical cancer. That is: (1671.68/2086) = 80.01%.
In other words, if one takes into account the relative contribution of each of the studies that examined the risk of OCP use in women under the age of 20 and the corresponding increased risk of cervical cancer, one would find an 80.01% increased risk.
This same technique was applied to the other categories of OCP use and the risk of cervical cancer to yield the results that OCP use prior to the age of 25 yielded a 64.51% increased risk in cervical cancer whereas longterm OCP use led to a 61.97% increased risk and the risk for "ever" versus "never" use was a 29.66% increased risk.
| Table 13E: | |||
|---|---|---|---|
| Risks for Women Who Used OCPS Before the Age of 20 | |||
| Author |
Percent Change
(A) |
Number of Patients
(B) |
Weighted Contributions
(A x B) |
| Brinton et al (10) | 46% increase* | 759 non-U.S. women | 349.14 |
| Brinton et al (11) | 28% increase* | 479: stock effect | 134.12 |
| Daling et al (13) | 130% increase* | 221 | 287.30 |
| Kjaer et al (16) | 30% increase* | 56: stack effect | 16.80 |
| Thomas et al (19) WHOs | 230% increase | 376 | 864.80 |
| Ursin et al (20) | 10% increase* | 196 | 19.50 |
| totals --> | --> --> --> | 2086 | 1671.68 |
| *This result reflects a trend toward an increased or decreased risk but does not attain statistical significance. | |||
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