Yes. Whittemore et al [29] also noted that white women who had "ever breastfed" had about a 19% decreased risk of ovarian cancer which continued to decrease for every month that a woman breastfed. Gwinn et al [30] noted that women who breastfed for more than a cumulative length of 2 years had a 70% decreased risk in ovarian cancer.
They appear to apply. John et al [33] found that black women who had four or more children had a 47% decreased risk of ovarian cancer. Women who breastfed for at least 6 months had a 15% reduction and women who used OCPs for 6 years or longer had a 38% decreased risk.
Yes. Usually when doctors speak about ovarian cancer they are speaking about a particular type called "epithelial ovarian cancer" which is the most common type. Nonepithelial cancers comprise about 7% of the rest of the malignant ovarian cancers. The two main types of non-epithelial cancers are called germ cell and stromal cell ovarian cancers. They both tend to occur in younger women. Oral contraceptives increase the trend toward developing a germ cell tumor: 2.0 (0.77-5.10) and reduce the risk of stromal cell tumors by 63%: [RR=0.37 (0.16-0.83)] according to one collaborative study [33].
The results presented here indicate that OCP use increases the risk of breast cancer, cervical cancer, and liver cancer, whereas they decrease the risk of uterine and ovarian cancer. In order to estimate the overall risk we must admit that no one really knows what the long-term effect of early OCP use is on any of these cancers. That is, we do not know if the trend for an increased risk in breast cancer or the decreased risk in ovarian cancer from early OCP use will get bigger or smaller as women approach their 60s and 70s. Because women are taking OCPs for longer periods of time and earlier in their lives the appropriate question to ask is:
Do women who use OCPs for 4 or more years before their first full-term pregnancy (FFTP) sustain an overall risk of more or less cancers if we base our answer on studies that predominantly take their information after 1980? (data taken from American Cancer Society: [1])
| Table 14E: | ||||
|---|---|---|---|---|
|
Cumulative Effect Of Long-Term*
Early OCP Use On The Total Number Of Reproductive Cancers In The USA |
||||
| Type of Cancer | Number of Cases from 1996 Estimate | Number of Deaths from 1996 Estimate | Estimated Rate of Increase or Decrease | Number of Additional or Reduced "Cases" |
| Breast Cancer | 184,300 | 44,300 | 44% to 72% increase | + 59,400 to 97,200 |
| Cervical Cancer | 15,700 | 4,900 | 50% increase | + 5,750 |
| Ovarian Cancer | 26,700 | 14,800 | 50% decrease | - 9,779 |
| Uterine Cancer | 34,000 | 6,000 | 50% decrease | - 12,452 |
| Total | +42,919 to 80,719 | |||
| * Long-term use is defined as at least 5 years of use, not necessarily before a first full-term pregnancy. | ||||
If one takes the statistics from the 1976 to 1980 database regarding early OCP use in women under the age of 24, one can estimate how many women used OCPs prior to their FFTP. (A detailed account of how the estimates were obtained is provided for at the end of this chapter). If the current trends continue, between 42,919 to 80,719 additional women will be expected to get cancer annually due to early, long-term OCP use as shown in Table 14E. The cumulative effect of early long-term OCP use is certainly negative.
| Table 14F: | ||||
|---|---|---|---|---|
|
Cumulative Effect Of Long-Term OCP Use*
On The Total Number Of Liver And Melanoma Cancers In The USA |
||||
| Type of Cancer | Number of Cases from 1996 | Number of Deaths from 1996 | Estimated Rate of Increase | Number of Additional Cases |
| Liver Cancer | 9,100 | 6,800 | 300% increase | + 19,997 |
|
Malignant
Melanoma |
16,500 | 2,700 | ? increase | ? |
| * Long-term use is defined as at least 5 years of use, not necessarily before a first full-term pregnancy. | ||||
Table 14F shows that if long-term OCP use truly increases the risk of liver cancer, then an additional 19,997 women will be expected to develop liver cancer annually in the U.S. in future years. A worldwide figure would be many times higher if the conservative estimate of a 300% increased risk ends up applying to women in Asia and Africa as well. It was noted earlier that if the rate of longterm OCP use in an Asian or African country is 20%, and if long-term OCP use truly does result in a 300% increased risk, an extra 60,000 women will get liver cancer each year, based on a sample size of 100 million women. If one includes a larger population by including the other Asian and African countries as well as other countries from around the world, one would note an increase of 300,000 "cases" per year for a population of 500 million women. The cure rate of liver cancer is very low; thus, many of these women would end up dying from their liver cancer. In addition, it will be extremely helpful if researchers perform a meta-analysis regarding long-term OCP use and the risk of malignant melanoma, because that would allow estimates of how many women would be at risk of developing malignant melanoma.
In addition to the elevated risks of breast, cervical, and hepatic cancer, OCP use carries an increased risk of other major side effects which include:
[[*It should be noted that today's low-dose OCPs may contain one of the new types of synthetic progestins called gestodene or desogestrel which apparently increase a woman's susceptibility to thrombosis (blood clots) [35].]]
Carson performed an overview of OCP use and osteoporosis, presenting both positive and negative studies [Journal of Reproductive Medicine, 1993]. Unfortunately, the two largest studies which were claimed to be positive were either too old (eg, the Goldsmith study in 1975) or had severe design errors. For example, Carson cites the Kleerekoper study [36] which found that women who did not take OCPs had a lower bone mineral density than women who did take OCPs. This study examined women ranging in age from 15 to 91 years old. This basically invalidates the study because most women over 60 years old never had the opportunity to take OCPs, therefore women with the least OCP use (ie, the older women) had the most osteoporosis. This type of error is called a failure to properly age-match. The study should have limited itself to studying women of the same age group (eg, women ages 52-55 years old) who would then theoretically have had similar exposures to OCP availability.
Other studies have suggested that OCP use plays a role in causing osteoporosis. Register et al [37] have noted that oral contraceptive use inhibits the normal acquisition of bone mineral in skeletally immature young adult female monkeys and Cooper et al [38], in a large British study, noted that women who took oral contraceptives actually had a statistically significant 20% increase in the occurrence of osteoporotic fractures in later life [RR = 1.20 (1.08-1.34)]. Few women have heard this information.
It was noted previously that injectable progesterone thins the vaginal mucosal lining and that the use of injectable progestins has been implicated in the transmission of HIV (Human Immunodeficiency Virus) in both monkeys [39] and in women in Thailand, Kenya, and Rwanda [40, 41]. Because OCPs contain artificial progestins, their use also might cause increased risk. Several studies support this. Allen et al [41] found that 38% of Rwandan women with HIV had used OCPs versus only 30% of women who did not use OCPs. Simonsen et al noted that prostitutes from Nairobi, Kenya, had an 80% increased risk of acquiring the HIV if they had used OCPs [42]. One study, by Mati et al [43] found a 50% (statistically non-significant) increase in the risk of HIV infection for women who took OCPs for more than 2 years. This study did not study prostitutes, but instead examined "women thought not to be of high-risk behavior." Because most of the women in this study were married and the number of sexual partners was low, one must question the validity of the study. Obviously, the latter study could fail to pick up the real risk of OCP use if a significant number of women who were faithfully married to a man who did not carry HIV, were on the Pill. These women would not get HIV, independent of whether or not they were using OCPs.
In addition, Mostad et al in the 1997 Lancet [44] reported that in a group of 318 Kenyan women who had the human immunodeficiency virus, those who were users of low-dose OCPs were 3.8 times more likely than women who did not use hormonal contraceptives to have HIV-1 cells in their cervical secretions whereas women who used high-dose OCPs were 12.3 times more likely to shed the virus. These women would theoretically be more likely to spread the virus.
For a population containing 200 million adults, it is estimated that 100 million will be female. Because the rate of liver carcinoma is 500 per 100,000 in certain Asian and African countries and because it occurs 4 times as frequently in men as in women, an annual incidence of 400,000 "cases" for men and 100,000 "cases" for women is predicted (ie, the rate in men is 400 per 100,000 and the rate in women is 100 per 100,000). Now if 20% of the women had used OCPs on a long-term basis (ie, 5 years or longer)*, (*In Brinton's study of OCPs, she noted that 37% of women took them for 5 years or more [45, p.830].) it would mean that 20 million women had used them on a long-term basis whereas 80 million had not. These 20 million women would now sustain a risk of 400 per 100,000 (ie, 4-fold their normal rate), and would be expected to develop 80,000 "cases" every year in addition to the 80,000 "cases" from the 80 million women who did not use OCPs on a long-term basis. Thus, in this sample population in which 20% of the women used OCPs on a longterm basis, one would expect 160,000 women to get liver cancer every year, which is 60,000 more than the figure of 100,000 which one would expect if no women took OCPs. This example is based on the predictions made for only one country of 200 million adults; its implications would have to be markedly increased for the cumulative populations of Asia and Africa. Often African or Asian women take injectable progestins instead of OCPs. If progestins end up causing a risk similar to that from OCP use, the above statistics would apply to those populations as well.
How were the data in Table 14E calculated? The estimates were made using data from Brinton's large study [45] as well as the cited statistic that currently about 10 million women in the U.S. are using OCPs. How can one estimate how many young women were using OCPs for 4 or more years prior to their first full-term pregnancy (FFTP)?
Brinton et al [45] noted in their study that 28.7% of women who had taken OCPs (520/1813) had taken them for 4 or more years prior to their FFTP. Two factors must be taken into account before estimating how many women took OCPs for 4 years or more prior to their FFTP. First, if there are currently 10 million women each year who took OCPs, it does not mean that over 4 years 40 million women will have used OCPs. Why? Because some women use OCPs for less than a year and some use them for several years. One cannot count the latter group as new women using OCPs each year or one would in effect "over count." Second, one must note that women have been using OCPs earlier in their lives and for longer periods of time today than back in the 1960s and 1970s [46, p.9S]. So instead of simply stating that 28.7% of all of the 10 million women using OCPs today are taking them for 4 years or more prior to their FFTP, it is conservatively estimated that 11.25% of women are. [One lowers the base projection by one-third to conservatively correct for over counting and multiplies by an additional 17.6% to account for the increased use of OCPs for longer periods of time at an early age today: (28.7% x 1/3 x 1.176 = 11.25%)]. In order to calculate how many additional breast cancer cases will be caused by early long-term OCP use in the U.S., one multiplies 1.125 million (11.25% x 10 million) by 12% (ie, today's life-time breast cancer risk is conservatively estimated at 12%), which yields the number 135,000. This is the number of breast cancer cases that would be expected to develop in a group of 1.125 million women over a lifetime. If one multiplies 135,000 by either 44% or 72% (which is the estimated increased risk of breast cancer for 4 years of OCP use prior to a FFTP), one obtains 59,400 to 97,200, which represents the number of additional cases of breast cancer due to early long-term OCP use.
In order to calculate the estimated number of cases for each of the other cancers, one simply multiplies the number of women at risk (ie, 1.125 million) by the expected prevalence of the cancer. The expected prevalence for cervical cancer would be a fraction of the rate of breast cancer. Because there were 15,700 cases of cervical cancer and 184,300 cases of breast cancer, cervical cancer has an incidence of: 15,700/184,300 or 0.0852 times the prevalence of breast cancer. Because about 12% of the female population will obtain breast cancer over a lifetime, it means that roughly 12% x 0.0852 or 1.0222% of the female population will get cervical cancer over a lifetime. Multiplying 1.0222% by the number of women at risk (1.125 million) yields 11,500 which is the expected number of these women who would normally get cervical cancer over a lifetime. Multiplying this by a 50% increased risk yields a number of 5,750 which is the expected number of new "cases" of cervical cancer that one would see using an estimate of 50% increased risk for women who took OCPs for 4 years or more prior to their FFTP.
Four years of OCP use would be expected to prevent ovarian cancer and so in the same way one can calculate that 9,779 "cases" of ovarian cancer would be prevented as well as 12,452 "cases" of uterine cancer. The total number of new "cases" would then be (59,400 to 97,200) + 5,750 9,779-12,452 = (42,919 to 80,719) new cases of cancer in women due to long-term early OCP use.
The additional cases of liver cancer were not included in this projection, but if one notes that at least 1.125 million women would be at risk for using OCPs for 5 years or longer (despite the longer length of time of 5 years used here, this statistic no longer specifies that the OCP use be before a FFTP so at least this many women would be at risk), one would find that an additional 19,997 cases of liver cancer would be expected to develop annually in future years based on a 300% increased risk (ie, 9100/ 184,300 *135,000*300%=19,997). Unfortunately, the decrease in liver cancer that might be expected due to a decrease in the hepatitis incidences in modern countries, may be offset by the increase due to early long-term OCP use.
1 Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer, J Clin. 1999; 49: 33-64. [Back]
2 Fauci AS, et al. Harrison's: Principle of Internal Medicine. 14th ed. New York: McGraw Hill; 1998. [Back]
3 Parkin, et al. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer. 1988; 41: 184-197. [Back]
4 Stanford JL. Combined oral contraceptives and liver cancer. Int J Cancer. 1989; 43: 254-259. [Back]
5 Kenya PR. Oral contraceptive use and liver tumours: a review. East African Medical Journal. 1990; 67:146-153. [Back]
6 Prentice RL. Epidemiologic data on exogenous hormones and hepatocellular carcinoma and selected other causes. Preventive Medicine. 1991; 20: 38-46. [Back]
7 Tavani A, et al. Female hormone utilisation and risk of hepatocellular carcinoma. Br J Cancer. 1993; 67: 635-637. [Back]
8 Rabe T, et al. Liver tumors in women on oral contraceptives. The Lancet. 1994; 344: 1568-1569. [Back]
9 Ory HW, et al. Combination oral contraceptive use and the risk of endometrial cancer. JAMA. 1987; 257: 796-800. [Back]
10 Levi F, et al. Oral contraceptive and the risk of endometrial cancer. Cancer Causes and Control. 1991; 2: 99-103. [Back]
11 Jick S, et al. Oral contraceptives and endometrial cancer. Obstet Gynecol. 1993; 82: 931-935. [Back]
12 Stanford JL, et al. Oral contraceptives and endometrial cancer: Do other risk factors modify the association? Int J Cancer. 1993, 54: 243-248. [Back]
13 Palmer JR. Oral contraceptive use and gestational choriocarcinoma. Cancer Detection and Prevention. 1991; 15: 45-48. [Back]
14 Osterlind A. Hormonal and reproductive factors in melanoma risk. Clinics in Dermatology. 1992; 10: 75-78. [Back]
15 Adam SA, Sheaves JK, et al. A case-control study of the possible association between oral contraceptives and malignant melanoma. Br J Cancer. 1981; 41: 45-50. [Back]
16 Gallagher RP, Elwood JM, et al. Reproductive factors, oral contraceptives and risk of malignant melanoma: Western Canada melanoma study. Br J Cancer. 1985; 52: 901-907. [Back]
17 Beral V, Evans S, et al. Oral contraceptive use and malignant melanoma in Australia. Br J Cancer. 1984; 50: 681-685. [Back]
18 Hannaford PC, et al. Oral contraceptives and malignant melanoma. Br J Cancer. 1991; 63: 430-433. [Back]
19 Helmrich S, Rosenberg L, et al. Lack of elevated risk of malignant melanoma in relation to oral contraceptive use. J Natl Cancer Inst. 1984; 72: 617-620. [Back]
20 Holly EA, Weiss NS, et al. Cutaneous melanoma in relation to exogenous hormones and reproductive factors. J Natl Cancer Inst. 1983; 70: 827-831. [Back]
21 Holly E, Cress R, Ahn DK. Cutaneous melanoma in women. Am J Epidemiol. 1995; 141: 943-950. [Back]
22 Le MG, Cabanes PA, et al. Oral contraceptive use and risk of cutaneous malignant melanoma in a case-control study of French women. Cancer Causes and Control. 1992; 3: 199-205. [Back]
23 Osterland A, et al. The Danish case-control study of cutaneous malignant melanoma Int J Cancer. 1988; 42: 821-824. [Back]
24 Palmer Jr, et al. Oral contraceptive use and risk of cutaneous malignant melanoma. Cancer Causes and Control. 1992; 3: 547-554. [Back]
25 Westerdahl J, et al. Risk of malignant melanoma in relation to drug intake, alcohol, smoking and hormonal factors. Br J Cancer. 1996; 73: 1126-1131. [Back]
26 Hankinson SE, et al. A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet Gynecol. 1992; 80: 708-714. [Back]
27 Goldzieher JW. Are low-dose oral contraceptives safer and better? Am J Obstet Gynecol. 1994; 171: 587-590. [Back]
28 Rosenberg L, et al. A case-control study of oral contraceptive use and invasive epithelial ovarian carcinoma. Am J Epidemiol. 1994; 139: 654-661. [Back]
29 Whittemore AS. Personal characteristics relating to risk of invasive epithelial ovarian cancer in older women in the United States. Cancer Supplement. 1993; 71: 558-564. [Back]
30 Gwinn ML, et al. Pregnancy, breastfeeding and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol. 1990; 43: 559-568. [Back]
31 Whittemore AS et al. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 U.S. case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992; 136: 1184-1203. [Back]
32 Spiritas R, et al. Fertility drugs and ovarian cancer: Red alert or red herring: Fertility and Sterility. 1993; 59: 291. [Back]
33 John EM, et al. Characteristics relating to ovarian cancer risk: Collaborative analysis of seven U.S. case-control studies. Epithelial Ovarian Cancer in Black Women. J Natl Cancer Inst. 1993; 85: 142- 147. [Back]
34 Orthocept: Drug Insert. Ortho Pharmaceuticals. 1996. [Back]
35 Herman R. New birth control pills increase clotting danger. Pittsburgh Post-Gazette. June 3, 1997: F4. [Back]
36 Kleerekoper M, et al. Oral contraceptive use may protect against low bone mass. Arch Intern Med. 1991; 151: 1971-1976. [Back]
37 Register TC, et al. Oral contraceptive treatment inhibits the normal acquisition of bone mineral in skeletally immature young adult female monkeys. Osteo Int. 1997; 7: 348-353. [Back]
38 Cooper C, et al. Oral contraceptive pill use and fractures in women: a prospective study. Bone. 1993; 14: 41-45. [Back]
39 Marx PA, et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nature Medicine. 1996; 2: 1084-1089. [Back]
40 Ungchusak, et al. Determinants of HIV infection among female commercial sex workers in northeastern Thailand: results from a longitudinal study. J Ac Immune Defic Syn Hum Retro. 1996. 12: 500-507. [Back]
41 Allen S, et al. Human immunodeficiency virus infection in urban Rwanda. JAMA. 1991; 266: 1657-1663. [Back]
42 Simonsen, et al. HIV infection among lower socioeconomic strata prostitutes in Nairobi. AIDS. 1990: 139-144. [Back]
43 Mati, et al. Contraceptive use and the risk of HIV in Nairobi, Kenya. Int J Gynecol Obstet. 1995; 48: 61-67. [Back]
44 Mostad SB, et al. Hormonal contraception, vitamin A deficiency and other risk factors for shedding HIV-1 infected cells from the cervix and vagina. The Lancet. 1997; 350: 922-927. [Back]
45 Brinton LA, Daling JR, et al. Oral contraceptives and breast cancer risk among younger women. J Natl Cancer Inst. 6/7/1995; 87: 827-835. [Back]
46 Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: further results. Contraception. 1996; 34: Sl-S106. [Back]
1, 2,