The Link Between Original, High-Estrogen Birth Control Pills and Cervical Cancer

The birth control pill was first approved in the United States for contraceptive use in 1960. Today, it is a leading form of contraception in the U.S. and is generally considered a safe and effective method for preventing pregnancy. The pill can also be used to manage acne, menstrual disorders, and to help treat pelvic pain. In addition, there are several health benefits to taking the pill, such as decreased risk of ovarian and endometrial cancer.

Birth control pills prescribed today are very different than those prescribed in the 1960s and
are not even on the market now.

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The first birth control pill, Enovid, was a pharmaceutical goldmine for G.D. Searle. Other companies soon followed. By 1965 roughly 6.5 million women in the U.S. were taking an oral contraceptive.

Enovid was developed using laboratory-produced versions of two essential reproductive hormones, estrogen and progestin, to prevent ovulation. Ovulation results in the release of an egg cell, the female reproductive cell. If there is no egg cell present, then pregnancy will not occur. Today’s oral contraceptives work in a similar manner. Despite their similarity, the original birth control pill is quite different from the ones prescribed today. One of the major differences is the amount of hormones in each pill.

Enovid contained approximately 10 mg of progestin and 0.15 mg of estrogen. In contrast, today’s oral contraceptives contain 10 to 100 times more hormones1.

Enovid contained what are now considered dangerously high doses of progestin and estrogen. If scientists and physicians had followed modern clinical trial protocols, Enovid never would have been given FDA approval. Enovid was tested in the late 1950s, before safety and effectiveness of drugs were considered as separate factors in drug development. The clinical trials for Enovid had largely taken place in Puerto Rico2, and high doses of progestin and estrogen were used to make sure women did not become pregnant.

None of the women that completed the clinical trials became pregnant. However, the local physician managing patients for the study reported that many women displayed serious side effects, including dizziness, nausea, vomiting, and severe stomach pain. As a result, nearly a quarter of patients dropped out of the trial during the first year, and she strongly suggested the 10 mg progestin dose be reduced.

Unfortunately, these side effects were deemed to be “imaginary” and largely ignored, a common theme in the treatment of women by the male-dominated medical establishment at the time. In addition, the researchers leading the trials in the U.S. (Dr. Gregory Pincus, Dr. John Rock, and others) did not want to restart the entire testing process by testing lower doses, as this would require additional time and money3. Due to the successful outcome of the drug regarding pregnancy, the study was pushed forward, and by 1960 the drug was approved in the United States for contraception2.

The lack of robust and transparent clinical testing had major downstream impacts on the women taking the pill. Physicians weren’t aware of the risks and neither were their patients. Synthetic hormones were relatively new in the pharmaceutical world at the time, so physicians did not have experience with these medications. In addition, there were no product pamphlets with drug warnings or papers to sign when picking up a prescription as there are today.

As early as 1962, new reports of blood clotting had been linked to Enovid and reported to the FDA . Many women also experienced nausea, dizziness, and vomiting, although these were typically dismissed as psychological problems [1].

By 1970, mounting frustration, activism and epidemiological evidence led to Senate hearings on the safety of the birth control pill. These hearings prompted the FDA to order that all contraceptive pills include a product insert detailing potential side effects, a major improvement for women’s health.

These hearings weren’t sufficient to remove the high dose Enovid pills from the market. Although birth control pills suffered a short-term loss in sales after the hearing, within a year they had fully rebounded. By 1970 women had other options, many of which used lower doses of hormones. The FDA recommended prescribing these lower dose pills. But the10 mg Enovid pill was still on the market and many physicians continued to prescribe it due to brand loyalty and the assumption that it was safe.

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The link between heightened hormone levels and reproductive cancer was well established by 1970, but not completely understood. Dr. Stern and colleagues had published multiple studies using rats, in which loss of hormones seemed to inhibit tumor development [2-4]. They also studied the impact of birth control pills on cancer in rats and found that the Enovid-treated rats developed cancer more slowly [3, 5]. However, reports from other labs came to the opposite conclusion, making it difficult to arrive at a consensus (discussed in [3]). Further, it was impossible to make accurate predictions about human cancer risk from rat studies.

Throughout the 1970s, more clinical and epidemiological research was performed regarding the impacts of high-dose birth control pills. There were links to breast, cervical, and endometrial cancer, although these were challenging to study. Cancer may take several decades to develop, and the majority of women involved in these studies had been on the pill for less than ten years. There were very few non-biopsy, noninvasive, tests at the time to detect early-stage cancer. Doctors were relying on symptomatic or visible tumors in order to diagnose cancer in these studies. This led to conflicting results in highly respected journals and confusion in the medical field [6, 7].

At this time, Dr. Stern had published her groundbreaking work on how abnormalities in cervical cell shape and size, dysplasia, were early warning signs of cervical cancer development. These changes could be detected in women using the Pap test and confirmed with additional biopsy studies [8-13]. Dr. Stern reasoned that long-term monitoring of women with dysplasia, who also were taking birth control pills, could be useful in determining the association between the pill and cervical cancer.

Dr. Stern and her colleagues developed a rigorous study plan [14]. From the more than 11,000 women that came to the Los Angeles Country Family Planning Clinic between 1967 and 1971, they identified 6,000 patients that had never taken birth control pills, and enrolled interested patients into four groups:

1: Pill users that had dysplasia at the outset of the study by Pap test.
2: Pill users with normal cervical tissue by Pap test.
3: Non-users that had dysplasia at the outset of study by Pap test.
4: Non-users with normal cervical tissue by Pap test

They examined patients every six months by Pap test for up to seven years of follow-up study. At each collection interval, samples were ranked on a 100-point scale established by Dr. Stern in 1974 [2], in which 0 to 28 is normal, 29 to 62 is dysplasia, and 63 and up is cancer. They found that women with dysplasia that started the pill were six times more likely to develop cervical cancer as opposed to those not on the birth control pill (Group 3). This difference only became apparent when analyzing data from six years or more, suggesting that longer-term studies were crucial to determine the impact of the high dose birth control pills on cancer.

These findings were published in Science in 1977 [14] and made big newspaper headlines, including the Washington Post. As this article points out, Dr. Stern’s study didn’t use the high dose Enovid pill. Nevertheless, this study was important in further linking hormonal changes to cervical cancer and supported additional long-term studies on the safety of oral contraceptives.

Follow-up work, with larger sample sizes, demonstrated that lower dose birth control pills were safe, effective and actually helped prevent many types of cancer, similar to the results Dr. Stern had first reported in her rat studies. In contrast, long term use of high-dose pills continued to be linked to breast and cervical cancer although these results varied, underscoring the complicated nature of clinical research.

Yet higher dose birth control pills, including 10 mg Enovid, still accounted for nearly 50% of annual sales as late as 1983. Finally, in 1988, G.D. Searle and other high-dose pill manufacturers announced that they would no longer be producing these drugs at the urging of the FDA.

Although this research was not Dr. Stern’s main focus, this work had a significant impact. She brought attention to negative long-term consequences that were not fully investigated prior to the drug’s release in the 1960s. This work also brought to the forefront the necessity of tissue screening for early-stage cervical cancer diagnosis and monitoring.

Today’s birth control pills contain significantly lower doses of hormones and their safety is well-established.

Footnotes:

1Women also have more options with progestin-only pills, low-dose pills, monophasic vs. multiphasic, extended cycle pills (women only get a period 4 times per year) as well as non-pill options like the IUD. Read more here.

2The development of the original birth control pill and subsequent clinical trials were largely run by Harvard scientist Dr. Gregory Pincus and physician Dr. John Rock with support from reproductive rights activist Margaret Sanger and philanthropist/activist Katherine McCormick. Read more here.

3Most of the funding of these studies came from individual donors such as Katherine McCormick rather than major pharmaceutical companies.

Newspaper Articles and Reviews:

PBS has several articles on this topic, including a timeline, details on the side effects of Enovid, the clinical trials performed in Puerto Rico, history on the involvement of G.D. Searle, and a review of the 1970 Senate hearings.

An historical perspective on the release of the birth control pill in the U.S. and the U.K. was written by Drs. Suzanne White Junod and Lara Marks. Read it here.

Another article on the controversial aspects of the development of Enovid, including the Puerto Rican clinical trials, can be found in the Harvard Crimson. Read it here.

A review of the people involved in the development of the birth control pill including Dr. Gregory Pincus, Dr. John Rock, Margaret Sanger, and Katharine McCormick can be found here.

A review from the US Department of Health and Human Services, Office on Women’s Health: 30 Achievements in Women’s Health in 30 Years (1984-2014) can be found here.

References:

1. Liao PV, Dollin J. Half a century of the oral contraceptive pill: historical review and view to the future. Can Fam Physician. 2012;58(12):e757-60. PubMed PMID: 23242907.
2. Stern E, Mickey MR. Neural mechanism in induction of dioestrus and tumour in the androgen sterile rat. Nature. 1967;216(5111):185-7. PubMed PMID: 6069882.
3. Stern E, et al. Neuroendocrine factors in experimental carcinogenesis. Ann N Y Acad Sci. 1969;164(2):494-508. PubMed PMID: 5260542.
4. Stern E, et al. Tumorigenesis in the androgen-sterile rat: reciprocal incidence of carcinogen induced-mammary gland and ovarian tumors. Rass Neurol Veg. 1967;21(1):99-117. PubMed PMID: 5617808.
5. Stern E, Mickey MR. Effects of a cyclic steroid contraceptive regimen on mammary gland tumor induction in rats. Br J Cancer. 1969;23(2):391-400. PubMed PMID: 5788048.
6. Brinton LA, et al. Long-term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer. 1986;38(3):339-44. PubMed PMID: 3744592.
7. Khoo SK. Cancer risks and the contraceptive pill. What is the evidence after nearly 25 years of use? Med J Aust. 1986;144(4):185-90. PubMed PMID: 3511357.
8. Stern E. Epidemiology of dysplasia. Obstet Gynecol Surv. 1969;24(7 Pt 2):711-23. PubMed PMID: 5212425.
9. Stern E. Cytological screening for cervical cancer; comparative findings in a 6 year survey of a well population. Cancer. 1958;11(1):122-6. PubMed PMID: 13500307.
10. Stern E. Cytohistopathology of cervical cancer. Cancer Res. 1973;33(6):1368-78. PubMed PMID: 4718680.
11. Stern E, et al. A cytological scale for cervical carcinogenesis. Cancer Res. 1974;34(9):2358-61. PubMed PMID: 4843536.
12. Stern E, Neely PM. Dysplasia of the Uterine Cervix. Incidence of Regression, Recurrence, and Cancer. Cancer. 1964;17:508-12. PubMed PMID: 14136534.
13. Stern E, Neely PM. Carcinoma and Dysplasia of the Cervix: A Comparison of Rates for New and Returning Populations. Acta Cytol. 1963;7:357-61. PubMed PMID: 14074943.
14. Stern E, et al. Steroid contraceptive use and cervical dysplasia: increased risk of progression. Science. 1977;196(4297):1460-2. PubMed PMID: 867043.