The following simple questions that were asked of the researchers at Harvard have never been answered:
How might the estrogen or the progestin either individually or jointly cause breast cancer?
(The following is a fairly technical answer and may be skipped without loss of continuity).
This is a very difficult question. Researchers know that the cancer cell is first formed by the influence of a carcinogen in a process called initiation and then continues to grow and be influenced by promoters (ie, those risk factors that promote the growth of cancerous breast cells). Many authors claimed that estrogen and progestins simply promote the growth of an already existing breast cancer cell. Others have theorized that they might also play a role as an initiator or as an "aid" to an initiator. The truth is, no one really knows. What we do know is that OCPs speed up the rate of breast cell division in nulliparous women, which would theoretically leave breast cells susceptible to the initiation process. We also know that hormone levels at the cellular level may have little to do with the levels measured in the bloodstream. Hulka et al have noted that: "Aspirates from women with normal breasts or benign breast disease have estradiol and estrone levels 10-40 times higher than plasma levels." [32, p.1116]. In addition, "Synthetic estrogens and progestins may possess higher binding affinities for estrogen receptors and progesterone receptors than natural 17B-estradiol and progesterone" [33, p.286]. This means that the artificial hormones may be more concentrated than thought to be at the level of the breast cell and that we really do not know how potent they are on the cellular level. What happens when these artificial hormones interact with the hormone receptors on the individual breast cells? As one leading researcher told me confidentially: "(There is) no way to adequately assess the potency of the birth control pill on the in vivo breast."
In summary, "Three types of carcinogenic effects are theoretically possible. The oral contraceptives might act as an initiator and transform a normal cell into a cancer cell through mutation of the genome or alteration of its expression. The oral contraceptives might act as a co-initiator by increasing the division rate of breast cells rendering them more susceptible to chemical, viral or radiation carcinogenesis, all of which require DNA synthesis to establish genetic alteration. Oral contraceptives might act as a tumor promoter and promote the growth of already transformed but latent breast cancer cells." [34, p.765]
In addition to the evidence discussed, researchers in the 1980s began to note that the progestins used in OCPs stimulated the growth of human breast cells. Specifically, norethindrone stimulated the growth of MRC-7 cells (ie, the name of a type of human breast cancer cell which has been grown in a culture dish by researchers)35. This is another point of concern because norethindrone was the most common progestin used in OCPs from 1964 to 1988 and is still used in some of today's OCPs such as OrthoNovum, Brevicon, Loestrin, Norinyl and Ovcon36. Jordan et al also noted that other progestins in addition to norethindrone (ie, norethynodrel, norgestrel and gestodene) all stimulated growth of the MRC-7 cells [37, p.1503], and Jeng et al (36) reported similar results. Another researcher named Longman (33) noted that the combination of ethinyl estradiol and norgestrel (eg, found in Ovral and Lo/Ovral) caused the greatest growth response in malignant breast cancer cells [33, p.284].
Table 5 in Brinton's paper [19, p.832] gives the raw data for women under the age of 45 who used OCPs for more than 6 months prior to their FFTP:
Page 33 of Rosenberg et al's study noted that of the women who were aged 25 to 44, a total of 52+23+136+34=245 "cases" used OCPs for more than 1 year prior to their FFTP whereas 86+30+86+39=241 "controls" did. In addition, 547 "cases" and 1014 "controls" had less than 1 year of OCP use before their FFTP. The odds ratio or estimated relative risk is thus: 245/547 divided by 241/1014 which comes to 1.884 or about an 88% increased raw risk for women aged 25 to 44 years old who used OCPs for more than 1 year prior to their FFTP.
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