Vol. 32, No. I, July 1979 Printed in U.8A.

FERTIUTY AND STERILITY Copyright © 1979 The American Fertility Society

ORAL CONTRACEPTIVES AND NEOPLASIA

GEORGE R. HUGGINS, M.D. ROBERT L. GIUNTOU, M.D. Division of Human Reproduction and Division of Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Combined estrogen-progestogen oral contraceptives have been available in the United States since 1960. The first compound approved contained 10 mg of norethynodrel and 150 145 ofmestranol. Current estimates of worldwide use range from 54 million to over 80 million and in the United States use is estimated at 8 million to over 10 million women. 1 Clearly, to justify such wide use of potent drugs, the risk-benefit ratio must weigh substantially in favor of the drug benefits. In the past 19 years over 30 brands of combined oral contraceptives have been sold in the United States. Today, they contain one of five synthetic progestogens (all derived from 19-nortestosterone) and one of two estrogens. 2 Most women are now using combined oral contraceptives with 0.3 to 1 mg of progestogen and 20 to 50 145 of estrogen. Since 1970 all of the newly introduced compounds have used ethinylestradiol as the estrogen fraction, and all but one have used norethindrone as the progestogen. One compound contains 0.3 mg of norgestrel,3 Outside the United States some of the 17 a-hydroxyprogesterone derivatives are in use. 3 However, these derivatives were withdrawn from the United States market in response to concerns regarding the occurrence of neoplastic lesions in dogs. Few issues evoke as much concern and controversy as does the suspected association between oral contraceptive use and the development of cancer. Isolated case reports and preliminary findings may give rise to overwhelming pressure to discontinue use of the drug with little attempt to weigh its possible risk-benefit ratios. This response is not confined to human evidence. Suspicion of carcinogenicity in any animal species has raised similar concerns and evoked the same demand for drug withdrawal,4

Other serious side effects such as cardiovascular problems with use of the oral contraceptives and severe pelvic infections with use of intrauterine devices have extensive documentation. Morbidity and mortality rates have been estimated. 5-7 By and large the response of the public and the medical profession has been to evaluate the risk-benefit ratio of contraceptive therapy as related to unplanned pregnancy or induced abortion and to accept the much lower risk of these very effective methods of contraception. We will survey some of the available data and attempt to evaluate possible associations between oral contraceptives and human neoplasia in light of pregnancy risk or benefit of oral contraception. PROBLEMS OF INVESTIGATION

This investigation is confounded by several problems: (1) there is no suitable animal model in most cases; (2) there is generally a long lag-time, approximately 15 years following exposure to a carcinogen until the development of overt malignancy8; (3) there is a low incidence of malignant disease in the young female population; and (4) there are multiple etiologic influences such as genetic, cultural, geographic, and environmental exposure to many possible carcinogens. Each steroid formulation used for contraception undergoes extensive testing in several animal species prior to human investigative use. These animal studies provide only presumptive evidence of carcinogenic potential within a single species and sometimes a single strain within the species. 8-12 Extrapolation of conclusions from one species to another has dubious validity. Neither positive nor negative results with animal exposure to suspected carcinogens can be used with any 1

HUGGINS AND GIUNTOLI

2

degree of certainty in relation to the human. The reader is referred to the George Washington University Center Population Reports, 6 which provide an extensive review of animal studies with sex steroids and their relationship to benign or malignant neoplasia. Animal studies are not discussed in detail in this paper. The relationship of oral contraceptives to benign neoplasms is germane because some benign neoplastic lesions may predispose or progress to frank invasive cancer. This is especially true with dysplasia of the cervix, hyperplasia of the endometrium, and, to some extent, benign dysplastic breast disease. INVESTIGATIVE METHODS

The principal investigative methods in humans include various epidemiologic approaches 6 (Table 1). The methodologies most frequently used are (1) case reports (tumor registries), (2) disease rates and trends, (3) case-control studies, and (4) cohort studies. Each of these approaches provides a specific piece of a very complex puzzle. None of these methods taken by themselves will provide a definitive answer as to causal relationships between exposure to an environmental carcinogen and the occurrence of disease. Needless to say, one would be unrealistic to ignore increasing and consistent evidence which is confirmed by these multiple approaches.

July 1979

Case Reports The case report (registry) method has served well to alert us to the appearance of new and hitherto unsuspected disease entities. In 1971 Herbst et al. I3 first reported the occurrence of vaginal adenosis and adenocarcinoma in daughters born to women who had taken diethylstilbestrol during early gestation. More recently, Baum et al. I4 reported the occurrence of benign liver tumors in oral contraceptive users. These initial reports provided the impetus for retrospective case-control and prospective cohort studies. As a result of these efforts, the association of maternal diethylstilbestrol ingestion, adenosis, and adenocarcinoma of the vagina in offspring is well established. The question ofliver tumors in oral contraceptive users is currently under intensive investigation. No conclusions regarding either the incidence of disease or risk of developing the disease can be determined by using only case reports or surveys.

Disease Rates and Trends Disease rates for specific malignancies are available for a number of differing populations. IS Their incidence varies widely according to geographic location and other subgroups (Table 2). Care must be taken not to extrapolate data to other (dissimilar) populations. This particular approach has been of limited usefulness in evaluating the influence of any single etiologic factor on the de-

TABLE 1. Four Epidemiologic Methods Used in Studying Oral Contraceptives and Neoplasia' Method

Case reports

Disease rate trends

Case-comparison studies

Cohort studies

Description

Describe patients, their illnesses, and exposures to environmental factors; discuss suspected interrelationships Examine the incidence or mortality of a disease in a large popUlation

Functions

Often the source of first suspicions about disease causes; encourage more rigorous study

Limitations

Few conclusions are made on the basis of case reports alone

To produce detectable changes in Can be compared with trends rates, exposure to environin exposure to environmental mental factor must be widefactors; help assess impact spread in the population and of disease on public must alter the chances of dehealth veloping the disease considerably Determine relative differences Do not determine the incidence Compare exposure to environrate in either group; depend mental factor in groups with in exposure between those on records of participants, a disease with that in simiwith and those without a diswhich may be faulty lar groups without the disease; appropriate when the ease disease is rare or quick results are desired Compare disease incidence in Appropriate when fullest infor- Often require study of large groups over long periods of mation, least subject to ungroups exposed to an environtime, especially with rare avoidable possibilities of mental factor with that in methodologic bias, is groups not exposed diseases required or when information on more than one disease is sought

3

ORAL CONTRACEPrIVES AND NEOPLASIA

Vol. 32, No.1

TABLE 2. Reported Annual Incidence of Cancers of Selected Sites/100,000 Women in Selected Countries, 1960s and 1970s 15 Country Site of cancer Nigeria

Breast Uterine cervix Uterine corpus Ovarya

5.8 7.0 0.5 3.0

United States

Israel

India

Japan

89.9 11.4 22.4 15.5

57.6 4.6 11.2 13.4

11.3 14.3 0.7 2.7

14.1 15.2 1.3 3.0

aIncludes tube.

velopment or progression of cancer. It will, however, monitor dramatic changes such as those which have taken place with regard to the increasing incidence of carcinoma of the lung in women. 16 Female Breast Cancer

The data for the United States show little change over the years for white females, although information from cancer registries implies a recent increase in older women. The incidence rates in black women appears to be increasing significantly.7, 16 Subpopulation groups may show more marked changes in disease rates, such as the apparent increasing rate of carcinoma of the breast in Marin County, California (1960--1973),11 Cancer of the Uterus Cervix. In New York and Connecticut the trend for invasive cancer of the cervix shows a steady decrease in the age-adjusted rate for all ages. The trend for in situ carcinoma of the cervix shows a steady increase in the age-adjusted rate for all ages. IS, 19 Corpus. The Third National Cancer Survey20 indicates a modest decline in the rate of incidence of corpus uteri cancer. This statistic was confirmed by both the New York and Connecticut registries. 21 Cancer of the Ovary

The incidence rates for ovarian cancer have remained about the same over the past 20 years. IS The rates for all ages declined slightly in the Third National Cancer Survey.20

who are disease-free. Factors such as age, parity, race, social class, sexual activity, drug use, concurrent disease, and elimination of exposure to other possible carcinogens are most important in assuring that the populations studied are as similar as possible. The use of oral contraceptives is then compared for both cases and controls. Failure to match for one or more variables can lead to major invalid hypotheses. The conclusions are usually expressed as relative risk or risk ratio. This is based upon the ratio between the incidence of the disease among the cases and the incidence among the controls. With this methodology a relative risk value of 1 would imply neither a positive nor a negative effect of exposure. A relative risk of 1 a positive association with exposure to oral contraceptives. In this type of study, highly positive relative risk figures may give rise to unwarranted alarm because the incidence of the disease in the general population is not defined. Five times relative risk for a disease with an incidence of 5/1,000 has more important implications than five times relative risk in a disease with a baseline incidence of 5/1,000,000. Unfortunately, case-comparison studies when reported in both the lay and scientific press may not clearly delineate the baseline risk. The potential exists for overestimating the absolute risk to the patient. Case-comparison studies are relatively inexpensive, can be done quickly, and can be carried out at single institutions which are able to obtain necessary numbers of patients with rare or lowincidence diseases.

Cohort Studies Case-Control Studies The main source of useful retrospective information regarding the association between contraceptive steroid exposure and the risk of neoplasia is found in the analysis of case-control studies. 22-29 The approach in case-control or case-comparison studies is to identify patients with the disease to be studied and to match them carefully with patients

The prospective cohort study compares the incidence of disease in patients who are exposed to the suspected environmental factor with other patients who are not so exposed. Cancer has a low incidence among women of reproductive age. The study of possible carcinogenic effects of oral contraceptives requires large numbers of patients followed over a long period of time in order to gather

4

HUGGINS AND GIUNTOLI

TABLE 3. Minimal Samples Required To Detect Differences in Disease Rates between Oral Contraceptive (OC) Users and Controls in Prospective Study 29 Site of cancer

No. of years after onset of study

Annual incidence rate in CODtrols/lO,OOO

Persons required in each group: incidence 2 times in OC users

Breast Corpus uteri Cervix

1 1 1

2.2 0.3 3.1

85,000 600,000 60,000

Breast Corpus uteri Cervix

10 10 10

7.5 1.3 5.6

25,000 140,000 35,000

enough information for adequate statistical analysis 23. 24. 26. 28. 29 (Table 3). The cohort study can define the baseline incidence of the disease and compare incidence among users and nonusers in a single population. The cost and logistical problems involved in adequately conducting a contraceptive cohort study has limited their number. At the present time there are four large contraceptive cohort studies in progress-two in the United States and two in the United Kingdom. These are referred to repeatedly in this survey30-34 (Table 4). Care must be taken not to extrapolate data to other (dissimilar) populations. For instance, subjects in the population of the Oxford Family Planning Study32 were white, married, economically middle class, and 25 to 39 years old at time of enrollment in the study. Conclusions regarding carcinoma of the breast in this population may have little significance for women in India or Japan.

July 1979 ORAL CONTRACEPrIVES AND BREAST DISEASE

Risk Factors in Carcinoma of the Breast Several major risk factors for carcinoma of the breast have been identified35 ,36 (Table 5). The marked predisposition for this disease in the female is attributed largely to the endocrine influence of estrogen on breast tissue. Breast cancer has occasionally been reported in males treated with long-term exogenous estrogen for carcinoma of the prostate37 or in male to female transsexuals receiving supplemental estrogen. 38 Postmenopausal use of estrogen may significantly increase the risk39 of developing carcinoma of the breast. The genetic predisposition is stronger in families with several relatives involved, especially if the disease has been premenopausal and bilatera1.40-42 In some populations of women with breast cancer, wet type cerumen (earwax) has been found to be twice as common as the dry type. Petrakis 43 believes that this significance is based on simple Mendelian inheritance of a specific apocrine gland type which produces wet rather than dry cerumen. This genetic typing apparently alters the breast apocrine gland tissue, contributing in some undefined fashion to increased risk of breast cancer. The strongly positive relationship with benign breast disease or precancerous mastopathy is most important because ofthe high incidence of benign breast disease in the general population and the considerable difficulty in defining which type of benign breast neoplasia is "precancerous."44-51

TABLE 4. Cohort Studies of Oral Contraceptive Use: Background Information 34 No. of women at enrollment Investigator, year, period of enrollment

Nature of study

Woman-years of observation

Age range (yr)

Current or ex-users

Nonusersn

Current users

Ex-users

9,803

Royal College of General Practitioners,3o 1974 (subjects enrolled during 1968-1969)

Practicebased

15-49

23,611

22,766

34,875

Ory et al.,31 1976 (subjects enrolled during 1970)

Populationbased

25-49

18,646

50,491

-40,368-

Vessey et al.,32 1976 (subjects enrolled during 1968-1974)

Clinic-based

25-39

9,653

7,379

-31,076-

Walnut Creek Contraceptive Drug Study,33 1974 (subjects enrolled during 1968-1972)

Health plan membershipbased

Nonusers n

Total

42,306

86,984

109,310

149,678

10,014

55,829

(IUD)

14,739 (diaphragm) 18-54

9,103

5,238

-24,344-

13,029

37,373

-------------------ORAL CONTRACEPI'IVES AND NEOPLASIA

Vol. 32, No.1

TABLE 5. Major Risk Factors in Breast Cancer35 Risk factor

Rstio

Comparison

Sex Age Genetic predisposition Family history of breast cancer Mother and sister; bilateral and premonopausal Wet type cerumen (earwax) Previous benign breast disease Precancerous mastopathy Previous cancer of one breast Parity (reflects early first parity) Age at first birth Lactation

99:1 85%:15%

Male >40

Yes

No

3:1

Yes

No

9:1

Yes

No

2:1

Yes

No

3:1

Yes

No

5:1

Yes

No

5:1

Breast Cancer and Chronic Mastitis

Nulliparous Parous

3:1

Late (>34) Early (18)

4:1

Yes

1:1

Benign breast disease is not a single welldefined process. The histologic descriptive terminology is sometimes confusing and inconsistent. Fibrosis, fibrocystic disease, cystic mastitis, adenosis, fibroadenoma, hypermetaplastic disease, and intraductal papillomas are terms used in discussions of benign breast disease. 56 This inconsistency makes it difficult to compare accurately conclusions from various reports. The risk of breast cancer is increased in patients with chronic cystic mastitis or fibrocystic disease of the breast. 4 4-51 McDivitt et al.57 have shown a much higher risk of cancer associated with lesions having more marked degrees of atypia. Black and Chabon58 in 1969 proposed a grading system of progressive and atypical proliferative changes in a mammary duct system. These duct changes in sequence were given numerical ranking as follows: (1) control, (2) hyperplasia, (3) and (4) atypia, and (5) carcinoma in situ. An increased relative risk (5 times) for developing cancer was shown in atypia grades 3 and 4 as compared with grades 1 and 2. Kodlin et al. 56 studied 2931 women with at least one benign breast biopsy obtained at the KaiserPermanente Medical Center in Oakland, Calif., between 1948 and 1973. These patients were followed for an average period of 6.7 years. The incidence of breast cancer in these patients varied between 2.5 and 21.111000 person-year rate. According to the Black-Chabon atypia scoring system, the risk increased steadily from 2.5 for lesions classified as types 1 and 2 and 21.1 for type 5. Kodlin et al. 56 thought that "in general, it appears that looking at the relative risks with respect to population expectations, histology can identify groups of somewhat higher risk than epidemiology .... "56-60 Cole 61 suggested that when using the Black-Chabon grading scale we have the concept of two types of breast disease, one of which is premalignant and one of which is not.

No

Breast Cancer, Preclinical Phase The duration of preclinical or predetected breast cancer may extend over many years. Gullin0 52 has estimated this "latent" time on the basis of an assumed 100 days' doubling time for breast cancer cells (Fig. 1). Using this model, the major conclusion to be drawn from this estimate is that the clinical phase of breast cancer is by far the shortest phase in the natural history of the disease. Among the problems associated with this model are the realities that the tumor cells do not grow at a constant exponential rate and that a significant portion of the tumor is composed of stroma rather than epithelial cells. However, this assumption

100 DAYS DOUBLING TIME

Diameter em

3

... ... ...

-' 1012

CJ

0

II:

CD ~

4

5

6

7

8

0.5

1

9

10

11

12

13

YEARS OF GROWTH

1 kg

10'· 10' 10'

:::> 10'

has support from the studies of Spratt and Spratt, 53 Collins et al.,54 and Silvestrimi et al.5 5 This long latent, or predetection, phase raises our concerns over the effects of exogenous steroids on the predetected lesion. If the growth of these tumors is stimulated by oral contraceptive steroids, one possible effect would be the appearance of the lesions in younger women, and progression of the lesions, once clearly detected, would be enhanced. There are no firm epidemiologic data at present to support these concerns.

Female 36 months' use). This trend was statistically significant.

Cohort Studies of Cervical Neoplasia Vessey et al. 32 found no cases of cervical dysplasia among 4217 diaphragm users. The incidences of dysplasia among 3162 IUD users and 9653 oral contraceptive users were similar (0.28 and 0.3111000 woman-years, respectively, with only 12 cases recorded). No valid statistical analysis was possible with so few cases. The Royal College of General Practitioners3o reported on only "malignant neoplasm of cervix uteri." Two cases were observed in oral contraceptive takers, two cases among "ex-takers," and four cases among the non-oral contraceptive takers. These numbers were too small for statistical analysis. The Walnut Creek Study 33 involving 17,942 women observed for 37,373 woman-years initially reported a statistically significant association between carcinoma in situ and duration of oral contraceptive use. This analysis involved only 34 cases of carcinoma in situ and did not include analysis of age at first birth or sexual activity and number of sexual partners; it showed a weaker association which lost its statistical significance. 34 Stern et al. 191 reported a prospective study of 300 women with cervical dysplasia matched with 300 women with normal cervical smears. These patients were obtained from among 6000 women enrolled in a family planning clinic in Los Angeles, Calif. The combined oral contraceptive chosen for

ORAL CONTRACEPTIVES AND NEOPLASIA

Vol. 32, No.1

the study contained 100 fLg of mestranol and 1 mg of ethynodiol diacetate. Over 90% of the non-pill users chose an intrauterine device. The patients with dysplasia and their controls were followed with a Papanicolaou smear every 6 months. Total study period for observation was 7 years. In the sample of women with normal smears there was no evidence of a differential effect of the pill. The patients with dysplasia taking oral contraceptives (compared with nonusers) showed a significantly increased conversion of dysplasia to carcinoma in situ with extended use (over 6 years). Analysis was conducted using the life-table method and involved only 32 patients with more than 6 years' use. There was no suggestion of conversion from dysplasia to carcinoma in situ for use less than 6 years. At present, it would appear that combined oral contraceptives containing 50 fLg of estrogen and 1 mg of progestogen or less, used in low-risk populations, offer no significant risks for conversion from normal cervical epithelium to dysplasia or carcinoma in situ. High-risk populations (those patients with early sexual activity, multiple partners, high parity, or existent cervical dysplasia) taking combined oral contraceptives containing more than 50 fLg of estrogen and 1 mg ofprogestogen for a prolonged time may be at increased risk for progression from normal tissue to dysplasia to carcinoma in situ. There are no firm data to suggest an increased risk of progression to invasive carcinoma of the cervix. OVARIAN NEOPLASMS

Several studies have reported a lower incidence of functional ovarian cysts in oral contraceptive users versus nonusers.192-194 The cohort studies by Vessey et aP2 and Ory et aP1 reported no association between benign ovarian neoplasms and oral contraceptive use. The Royal College cohort studflO showed a decreased incidence of ovarian tumors in oral contraceptive users; however, functional cysts and true neoplastic lesions were not analyzed separately. OVARIAN CANCER

Few epidemiologic studies are available reporting ovarian cancer and oral contraceptive use. 194 ,195 The data presented are reassuring (although incomplete), demonstrating no increased incidence and no association between ovarian cancer and oral contraceptive use. Newhouse et

17

al.,195 in a case-comparison study of 300 women with ovarian cancer, suggested that oral contraceptive use might protect against ovarian cancer. These findings require confirmation from other diversified patient populations. CHORIOCARCINOMA

After initial evacuation of the hydatidiform mole, urine levels of human chorionic gonadotropin (HCG) fall rapidly, indicating absence offunctioning trophoblastic tissue. These titers should be negative within 2 weeks to several months after evacuation. Persistence of elevated HCG titers or a rising titer indicates persistent, functioning, trophoblastic tissue and may signal malignant change to choriocarcinoma. This change may take place in 2% to 10% of untreated patients. 195 Contraception is most important during the early months following treatment of hydatidiform mole. A pregnancy will produce HCG and confound attempts to detect persistent or recurrent disease. Because of the need for reliance on HCG assays, patients are advised not to establish a new pregnancy for the 1st year offollow-up c.fter treatment of hydatidiform mole. Stone et al. 196 investigated the influence of oral contraceptive therapy on the course of surgically treated hydatidiform moles. They found the need for chemotherapy for trophoblastic tumor after evacuation of a hydatidiform was significantly increased in patients taking oral contraceptives before normal HCG values were obtained. Oral contraception was also found to delay the decrease in HCG excretion in patients not requiring treatment with cytotoxic drugs (Table 11). Until this study can be confirmed or challenged, oral contraceptives should not be used in patients with positive HCG titers who have been treated for hydatidiform mole. SUMMARY

Combined oral contraceptives have been used by millions of women in the United States for almost 20 years. During this time, the steroid content of these pills has been reduced markedly from their high initial levels. All of the new formulations introduced in the last 9 years contain less than 50 fLg of ethinylestradiol and less than 1 mg of norethindrone. In the United States, because of the suspected association with neoplasia in animals, the 17-hydroxyprogesterones are not in use. Reports of an association between sequential oral

HUGGINS AND GIUNTOLI

18

TABLE 11. Relationship of Oral Contraceptives (OC) to Development of Tumor Requiring Chemotherapy l96 All patients

Patients requiring treatment with cytotoxic drugs No.

%

Patients not taking OC at any time Patients taking OC before HCGnormal Patients taking OC when HCGnormal

464

43

9.3

65

16

24.6

26

0

0

All patients

555

59

11.2

contraceptives and endometrial carcinoma have contributed to withdrawal of the sequential formulations from the United States market. The problems in investigating neoplasia and oral contraceptives include the following: (1) absence of a suitable animal model, (2) long lag-time from exposure to development of disease, (3) low incidence of specific neoplastic diseases, and (4) multiple etiologic factors in the study population. The principal investigative methods in the human are various epidemiologic approaches. The methodologies most frequently used are (1) case reports (tumor registries), (2) disease rates and trends, (3) case-comparison (retrospective) studies, and (4) cohort (prospective) studies. These methods cannot prove a causal relationship between exposure to a possible carcinogen and the occurrence of disease. Care must be taken not to extrapolate epidemiologic conclusions to dissimilar populations. Consistent evidence (positive or negative), confirmed by multiple epidemiologic approaches, can be used to guide physicians and regulatory agencies in formulating policy for the clinical use of oral contraceptives.

Breast Disease Both the progestogen-only and the combined oral contraceptives have been shown to have a protective effect on the development of benign breast disease. This protective effect does not appear until 2 years of use. Data at present are inadequate to predict persistence beyond 4 years of use. The protective effect appears to be due to the progestogen component. There may be at least two types of benign breast disease, one of which is premalignant and the other is not. The oral contraceptives appear to protect only against those benign lesions which are not premalignant, with few exceptions. Current epidemiologic data show no association

July 1979

(either adverse or beneficial) between oral contraceptive use and the development of carcinoma of the breast in women. There is need to better define patients at high risk for breast cancer and conduct appropriate studies on these sUbpopulations.

Liver Tumors Long-term combined oral contraceptive use appears to be related to the development of benign liver neoplasia. The risk increases with the dose of the steroid and the age of the user. These lesions are quite rare (1 to 5/1,000,000 women). They may be life-threatening because of potential spontaneous rupture and hemorrhage. The potential for rupture appears to be related to the histologic type of adenoma rather focal nodular hyperplasia. Standard blood liver function tests are of little value for screening diagnostic purposes. Physical examination, ultrasound, angiography, and liver scan are the most useful techniques for diagnosis. Biopsy and resection are attendant with significant risk of hemorrhage. There is some evidence that these lesions will spontaneously regress following discontinuation of the oral contraceptive. Pregnancy and resumption of use may exacerbate these lesions.

Endometrial Hyperplasia Long-term postmenopausal use of estrogens appears to increase significantly the risk of developing endometrial hyperplasia and adenocarcinoma of the endometrium. Sequential oral contraceptives (14 to 16 days of high-dose, unopposed estrogen followed by estrogen-progestogen for 5 or 6 days) were withdrawn from use in the United States in 1976. This action was in response to a few case reports of endometrial hyperplasia and adenocarcinoma occurring in young women taking these formulations. There is no suggestion that the use of combined oral contraceptives or progestogen-only pills may be associated with the development of endometrial hyperplasia or adenocarcinoma of the endometrium.

Leiomyomas Estrogens appear to be related to the growth of pre-existing uterine leiomyomas. The use· of lowdose combined oral contraceptives does not appear to increase significantly the risk of developing or increasing the growth of pre-existing leiomyomas.

ORAL CONTRACEPI'IVES AND NEOPLASIA

Vol. 32, No.1

Cervical Changes Endocervical cells under the influence ofprogestogens may develop adenomatous changes. Although benign, these changes have on occasion been misinterpreted as carcinoma. Analysis ofthe association between oral contraceptives and cervical neoplasia is especially difficult. The most important risk factors (age at first intercourse and number of sexual partners) are difficult to determine accurately. Most studies conducted prior to 1975 did not consider these factors. In several studies in which the data have been reanalyzed to take these factors into account, the conclusions have been altered. There appears to be no increased risk of developing cervical dysplasia or carcinoma in situ for low-risk populations of patients who use low-dose combined oral contraceptives. High-risk patients (early sexual activity, multiple partners, high parity, patients with existent cervical dysplasia) taking combined oral contraceptives containing more than 50 ILg of estrogen and 1 mg of progestogen for a prolonged period of time may be at increased risk for development of dysplasia or progression to carcinoma in situ. There are no firm data to suggest an increased risk of progression of such lesions to invasive carcinoma of the cervix.

Pituitary Neoplasia The use of radioimmunoassay for prolactin and poly tomography of the pituitary sella has markedly increased the ability to diagnose small pituitary tumors. At present, data are insufficient to establish any association between oral contraceptive use and pituitary neoplasia.

Choriocarcinoma Oral contraceptives may have an adverse association with resolution of hydatidiform mole. Patients should not use steroidal contraception until HeG titers are negative. Acknowledgments. We are grateful to Joby Jackson, Sharon Ricciarrdi, and Elizabeth Iannuzzi for their valuable technical assistance and typing in preparation of the manuscript. REFERENCES 1. Population Reports: Oral contraceptives: update on

usage, safety, and side effects. Baltimore, Population Information Program, Johns Hopkins University, 1979, p 133 2. Peel J, Potts M: Oral contraceptives. In Textbook of Contraceptive Practice. Cambridge, England, Cambridge University Press, 1970, p 95

19

3. Hatcher RA, Stewart GK, Stewart FS, Guest F, Stratton P, Wright AH: Contraceptive Technology. New York, Irvington Publishers Inc, 1978, p 41 4. Finkel MJ, Berliner VR: The extrapolation of experimental findings (animal to man): the dilemma of the systemically administered contraceptives. Bull Soc Pharmacol Environ Pathol 4:13, 1973 5. Tietze C, Bongaarts J, Schearen B: Mortality associated with the control offertility. Fam Plann Perspect 8:6,1976 6. Population Reports: Debate on oral contraceptives and neoplasia continues; answers remain elusive. Washington DC, George Washington University Medical Center, 1977, p 78, Ser A4 7. Population Reports: U.S. morbidity and mortality trends relative to oral contraceptive use 195&-1975. Washington DC, George Washington University Medical Center, 1977, pAl, Ser A4 [Suppl] 8. Hueper WC: Environmental cancer. In The Physiopathology of Cancer, Second Edition, Edited by F Homburger. New York, Hoeber, 1959, p 919 9. Committee on Safety of Medicines: Carcinogenicity Tests of Oral Contraceptives. London, Her Majesty's Stationery Office, 1972, p 23 10. Drill VA: Experimental and clinical studies on relationship of estrogens and oral contraceptives to breast cancer. In Experimental Model Systems in Toxicology and Their Significance in Man, Edited by WAM Duncan. Proceedings of the European Society for the Study of Drug Toxicity, Vol 15, Zurich, Switzerland, 1973. Amsterdam, Excerpta Medica Int Congr Ser 311, 1974, P 200 11. Rudali G, Coezy E, Chemama R: Mammary carcinogenesis in female and male mice receiving contraceptives or gestagens. J Natl Cancer Inst 49:813, 1972 12. Bern HA, Nandi S: Recent studies of the hormonal influence in mouse mammary tumorigenesis. In Progress in Experimental Tumor Research, Vol 2, Edited by F Homburger. New Yor k, Hafner Publishing Co, 1961, P 91 13. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878, 1971 14. Baum JK, Holtz F, Bookstein JJ, Klein EW: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926, 1973 15. Waterhouse J, Muir C, Correa P, Powell J (Editors): Cancer Incidence in Five Continents, Vol 3. Lyon, France, International Agency for Research on Cancer (IARC Scientific Publication No 15), 1976, 586 P 16. Seidman H, Sibberberg E, Holley A: Cancer statistics 1976: a comparison of white and black populations. CA 26:9,1976 17. Paffenbarger RS Jr, Fasal E, Simmons ME, Kampert JB: Cancer risk as related to use of oral contraceptives during fertile years. Cancer 39:1887, 1977 18. Silverberg E: Gynecologic cancer: statistical and epidemiological information. American Cancer Society Professional Educational Publication, 1975, p 16 19. Cramer DW, Cutler SJ, Cristine W: Trends in the incidence of endometrial cancer in the U.S. Gynecol Oncol 2:130,1974 20. Third National Cancer Survey: Incidence Data of the National Cancer Institute Monogr No 41, DHEW Publication No (NIH)75-787, Edited by SJ Cutler, SL Young. Washington DC, United States Government Printing Office, 1975

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21. Cramer DW, Cutler SJ: Incidence and histopathology of malignancies of the female genital organs in the US. AmJ Obstet GynecoI118:443, 1974 22. Cornfield J, Haenszel W: Some aspects of retrospective studies. J Chronic Dis 11(5):523, 1960 23. Doll R, Vessey MP: Evaluation of rare adverse effects of systemic contraceptives. Br Med Bull 26:33, 1970 24. Dorn HF: Some problems arising in prospective and retrospective studies of the etiology of disease. N Engl J Med 261:571, 1959 25. Hardy RJ, White C: Matching in retrospective studies. Am J Epidemiol 93:75, 1971 26. MacMahon B, Pugh TF: Epidemiology: Principles and Methods. Boston, Little, Brown and Co, 1970, 376 p 27. Sartwell PE: Retrospective studies: a review for the clinician. Ann Intern Med 81:381, 1974 28. Schlesselman JJ: Sample size requirements in cohort and case-control studies of disease. Am J Epidemiol 99:381, 1974 29. Seigel D, Corfman P: Epidemiological problems associated with studies of the safety of oral contraceptives. JAMA 203:148, 1968 30. Royal College of General Practitioners: Oral ContraceptivesandHealth.NewYork,PitmanPublishingCo, 1974 31. Ory H, Cole P, MacMahon B, Hoover R: Oral contraceptives and reduced risk of benign breast disease. N Engl J Med 294:419, 1976 32. Vessey MP, Doll R, Peto R, Johnson B, Wiggins P: A long-term follow-up study of women using different methods of contraception: an interim report. J Biosoc Sci 8:375,1976 33. Ramcharan S: The Walnut Creek Contraceptive Drug Study, A Prospective Study of the Side-Effects of Oral Contraceptives, Vol 1, DHEW Publication No (NIH). Washington DC, United States Government Printing Office, 1974 34. World Health Organization Technical Report Series: Steroid Contraception and the Risk of Neoplasia, No 619, 1978 35. Leis HP: Epidemiology of breast cancer: identification of the high-risk woman. In The Breast, Edited by HS Gallagher, HP Leis, RK Snyderman, JA Urban. Saint Louis Mo, CV Mosby Co 1978, p 38 36. Leis HP, Black MM, SaIl S: The pill and the breast. J Reprod Med 16:5, 1976 37. Holleb AI, Freeman HP, Farrow JH: Cancer of the male breast. NY State J Med 68:544, 1968 38. Symmers W St C: Carcinoma of breast in trans-sexual individuals after surgical and hormonal interference with the primary and secondary sex characteristics. Br J Med 2:83,1968 39. Hoover R, Gray LA, Cole P, MacMahon B: Menopausal estrogens and breast cancer. N Engl J Med 295:401,1976 40. Petrakis NL: Genetic factors in the etiology of breast cancer. Cancer 39:2709, 1977 . 41. Anderson DE: Some characteristics of familial breast cancer. Cancer 28:1500, 1971 42. Anderson DE: Genetic study of breast cancer: identification of a high risk group. Cancer 34:1090, 1974 43. Petrakis NL: Cerumen genetics and human breast cancer. Science 173:347, 1971 44. Warren S: The relation of "chronic mastitis" to carcinoma of the breast. Surg Gynecol Obstet 71:257, 1940 45. Monson RR, Yen S, MacMahon B: Chronic mastitis and carcinoma of the breast. Lancet 2:224, 1976

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46. Donnelly PK, Baker KW,.Carney JA, O'Fallon WM: Benign breast lesions and subsequent breast carcinoma in Rochester, Minnesota. Mayo Clin Proc 50:650,1975 47. Davis HH, Simons M, Davis JB: Cystic disease of the breast: relationship to carcinoma. Cancer 17:957, 1964 48. Black MM, Barclay THC, Cutler SJ, Hankey BF, Asire AJ: Association of atypical characteristics of benign breast lesions with subsequent risk of breast cancer. Cancer 29:338, 1972 49. Copeland MM: Precancerous lesions ofthe breast: how to treat them. Postgrad Med 27:332, 1960 50. Potter JF, Slimbaugh WP, Woodward SC: Can breast carcinoma be anticipated? A follow-up of benign breast biopsies. Ann Surg 167:829, 1968 51. Nomura A, Comstock GW, Tomascia JA: Epidemiologic characteristics of benign breast disease. Am J Epidemiol 105:505, 1977 52. Gullino PM: Natural history of breast cancer progression from hyperplasia to neoplasia as predicted by angiogenesis. Cancer 39:2697, 1977 53. Spratt JS Jr, Spratt TL: Rates of growth of pulmonary metastases and host survival. Ann Surg 159:161, 1964 54. Collins VP, Loefller RK, Tivey H: Observations on growth rates of human tumors. Am J Roentgenol Radium Ther Nucl Med 76:988, 1956 5. Silvestrimi R, Sanfilippo 0, Tedesco G: Kinetics of human mammary carcinomas and their correlation with the cancer and the host characteristics. Cancer 34: 1252, 1974 56. Kodlin D, Winger EE, Morgenstern NL, Chen V: Chronic mastopathy and breast cancer. Cancer 39:2603,1977 57. McDivitt RW, Hutter RV, Foote FW, Stewart FW: In situ lobular carcinoma, a prospective follow-up study indicating cumulative patient risks. JAMA 201:96, 1967 58. Black MM, Chabon AB: In situ carcinoma of the breast. Pathol Annu 4:185,1969 59. Shapiro S, Strax P, Venet L, Fink R: The search for risk factors in breast cancer. AmJ Public Health 58:820,1968 60. Zippin CC, Petrakis NL: Identification of high risk groups in breast cancer. Cancer 28:1381, 1971 61. Cole PT: Oral contraceptives and breast neoplasia. Cancer 39: 1906, 1977 62. Feinleib M: Breast cancer and artificial menopause: a cohort study. J Natl Cancer Inst 41:315, 1968 63. Hirayama T, Wynder EL: A study of the epidemiology of cancer of the breast: the influence of hysterectomy. Cancer 15:28, 1962 64. Lilienfeld AM: The relationship of cancer of the female breast to artificial menopause and marital status. Cancer 9:927, 1956 65. Trichopoulos D, MacMahon B, Cole P: Menopause and breast cancer risk. J Natl Cancer Inst 48:605, 1972 66. Stoll BA: Hypothesis: breast cancer regression under oestrogen therapy. Br Med J 3:446, 1973 67. Lacassagne A: Apparition de cancers de la mamelle chez la souris male, soumise a des injections de folliculine [the appearance of mammary cancer in male mice by injection of folliculine (FR)]. CR Acad Sci 195:630, 1932 68. Huggins C, Yang NC: Induction and extinction of mammary cancer. Science 137:257, 1962 69. Kirschner MA: The role of hormones in the etiology of human breast cancer. Cancer 39:2716, 1977 70. Lemon HM, Wotiz HH, Parsons L, Mozden PJ: Reduced estriol excretion in patients with breast cancer prior to endocrine therapy. JAMA 196:112, 1966

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71. Cole P, MacMahon B: Oestrogen fractions during early reproductive life in the aetiology of breast cancer. Lancet 1:604,1969 72. Brecher PI, Wotiz HH: Competition between estradiol and estriol for end organ receptor proteins. Steroids 9:431, 1967 73. Lemon HM: Endocrine influences on human mammary formation: a critique. Cancer 23:781, 1969 74. MacMahon B, Cole P, Brown JB, Aoki K, Lin TM, Morgan RW, Woo NC: Oestrogen profiles of Asian and North American women. Lancet 2:900,1971 75. Dickinson LE, MacMahon B, Cole P, Brown JB: Estrogen profiles or Oriental and Caucasion women in Hawaii. N Engl J Med 291:1211, 1974 76. Leis HP: Hormones in the epidemiology of breast cancer. Dis Breast 2:7, 1976 77. Brenner PF, Mishell DR, Stanczyk FZ, Goebelsmann U: Serum levels of d-norgestrel, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel. Am J Obstet Gynecol 129: 133, 1977 78. Hellman L, Zumoff B, Fishman J, Gallagher TF: Peripheral metabolism of 3H-estradiol and the excretion of endogenous estrone and estriol glucosiduronate in women with breast cancer. J Clin Endocrinol Metab 33:138,1971 79. Marmorston J, Crowley LG, Myers SM, Stern E, Hopkins CE: Urinary excretion of estrone, estradiol and estriol by patients with breast cancer and benign breast disease. Am J Obstet Gynecol 92:460, 1965 80. Papaioannou AN: Etiologic factors in cancer of the breast in humans. Surg Gynecol Obstet 138:257, 1974 81. Deshpande N, Carson P, Horner J: Oestriol in human breast tumors. J Steroid Biochem 7:11, 1976 82. Flood C, Pratt JH, Longcope C: The metabolic clearance and blood production rates of estriol in normal, nonpregnant women. J Clin Endocrinol Metab 42:1, 1976 83. Longcope C, Pratt JH: Breast cancer and estriol dynamics. Program of the Breast Cancer Task Force, Division of Cancer Biology Diagnosis, NIH, San Antonio, Texas, 1975, pp 62-63 84. Vessey MP, Doll R, Sutton PM: Oral contraceptives and breast neoplasia: a retrospective study. Br Med J 3:719, 1972 85. Arthes FG, Sartwell PE, Lewison EF: The pill, estrogens and the breast: epidemiologic aspects. Cancer 28:1391, 1971 86. Sartwell PE, Arthes FG, Tonascia JA: Epidemiology of benign breast lesions: lack of association with oral contraceptive use. N Engl J Med 288:551, 1973 87. Fasal E, Paffenbarger RS Jr: Oral contraceptives as related to cancer and benign lesions of the breast. J Natl Cancer Inst 55:767, 1975 88. Boston Collaborative Drug Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder and breast tumours. Lancet 1:1400, 1973 89. Kelsey JL, Lindfors KK, White C: A case-control study of the epidemiology of benign breast disease with reference to oral contraceptive use. Int J Epidemiol 3:333, 1974 90. Kelsey JL, Holford TR, White C, Mayer ES, Kitty SE, Acheson RM: Oral contraceptives and breast disease: an epidemiological study. Am J Epidemiol107:236, 1978

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91. Hoover R, Bain C, Cole P, MacMahon B: Oral contracep· tive use association with frequency of hospitalization and chronic disease risk indicators. Am J Public Health 68:335, 1978 92. Janerich DT, Glebatis DM, Dugan JM: Benign breast disease and oral contraceptive use. JAMA 237:2199,1977 93. Nomura A, Comstock GW: Benign breast tumor and estrogen hormones: a population-based retrospective study. Am J Epidemiol 103:439, 1976 94. Livosli VA, Stadel BV, Kelsey JL, Holford TR, White C: Fibrocystic breast disease in oral contraceptive users: a histopathological evaluation of epithelial atypia. N Engl J Med 299:381, 1978 95. Spencer JD, Millis RR, Hayward JL: Contraceptive steroids and breast cancer. Br Med J 1:1024, 1978 96. Horvath E, Kovacs K, Ross RC: Ultrastructural findings in a well differentiated hepatoma. Digestion 7:74, 1972 97. Baum JK, Holtz F, Bookstein JJ, Klein EW: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926, 1973 98. Edmondson HA: Atlas of Tumor Pathology. Washington DC, Armed Forces Institute of Pathology, 1958, Sect 7, p 18 99. Ameriks JA, Thompson NW, Frey CF, Appleman HD, Walter JF: Hepatic cell adenomas, spontaneous liver rupture and oral contraceptives. Arch Surg 110:548, 1975 100. Christopherson WM, Mays ET: Liver tumors and contraceptive steroids: experience with the first one hundred registry patients. J Natl Cancer Inst 58:167, 1977 101. Mays ET, Christopherson WM, Barrows GH: Focal nodular hyperplasia of the liver: possible relationship to oral contraceptives. Am J Clin Pathol 61:735, 1974 102. Mays ET, Christopherson WM, Mahr MM, Williams HC: Hepatic changes in young women ingesting contraceptive steroids: hepatic hemorrhage and primary hepatic tumors. JAMA 235:730, 1976 103. McAvoy JM, Tompkins RJ, Longmire WI> Jr: Benign hepatic tumors and their association with oral contraceptives: case reports and survey ofthe literature. Arch Surg 111:761, 1976 104. Nissen ED, Kent DR, Nissen SE: Etiology factors in the pathogenesis of liver tumors associated with oral contraceptives. Am J Obstet Gynecol 127:61, 1977 105. Vana J, Murphy GP, Aronoff BL, Baker HW: Study of association between liver tumors and oral contraceptive use. Unpublished data, 1977 106. Keifer WS, Scott JC: Liver neoplasms and the oral contraceptives. Am J Obstet GynecoI128:448, 1977 107. Edmondson HA, Henderson B, Benton B: Liver-cell adenomas associated with use of oral contraceptives. N Engl J Med 294:470, 1976 108. Nissen ED, Kent DR, Nissen SE, McCrae DM: The association of liver tumors with oral contraceptives. Obstet Gynecol 48:49, 1976 109. Armed Forces Institute of Pathology, Hepatic Branch and Center for Disease Control, Bureau of Epidemiology, Family Planning Evaluation Division: Increased risk of hepatocellualr adenoma in women with long-term use of oral contraceptives. Morbidity Mortality Weekly Rep 26:293, 1977 110. Garcia CR, Gordon J, Drill VA: Contraceptive steroids and liver lesions. J Toxicol Environ Health 3:197, 1977 111. Berg JW, Ketelaar RJ, Rose EF, Vernon RG: Hepatomas and oral contraceptives. Lancet 2:349, 1974

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112. Vessey MP, Kay CR, Baldwin JA, Clarke JA, MacLeod IE: Oral contraceptives and benign liver tumors. Br MedJ 1:1064, 1977 113. Edmondson HA, Reynolds TB, Henderson B, Benton B: Regression of liver cell adenomas associated with oral contraceptives. Ann Intern Med 86:180, 1977 114. Ramseur WL, Cooper MR: Asymptomatic liver cell adenomas: another case of resolution after discontinuation of oral contraceptive use. JAMA 239:1647, 1978 115. Anderson PH, Packer JT: Hepatic adenoma observations after estrogen withdrawal. Arch Surg 111:898, 1976 116. Kent DR, Nissen ED, Nissen SE, Ziehm DJ: Effect of pregnancy on liver tumor associated with oral contraceptives. Obstet Gynecol 51:148, 1978 117. Hibbard LT: Spontaneous rupture of the liver in pregnancy: a report of eight cases. Am J Obstet Gynecol 126:334, 1967 118. Kent DR, Nissen ED, Nissen SE, Chambers C: Maternal death resulting from rupture of liver adenoma associated with oral contraceptives. Obstet Gynecol 50:55, 1977 119. Baird IN, Hawley RG: Spontaneous rupture of the liver during pregnancy. J Reprod Med 6:93, 1971 120. Knowles DM, Casarella WJ, Johnson PM, Wolff M: The clinical, radiologic and pathologic characterization of benign hepatic neoplasms: alleged association with oral contraceptives. Medicine 57:223, 1978 121. Shearman RP: Amenorrhea after treatment with oral contraceptives. Lancet 2:1110, 1966 122. Kleinberg DL, Noel GL, FrantzAG: Galactorrhea: a study of235 cases, including 48 with pituitary tumors. N Engl J Med 296:589, 1977 123. Chang RJ, Keye WR Jr, Young JR, Wilson CB, Jaffe RB: Detection, evaluation, and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea. Am J Obstet Gynecol 128:356, 1977 124. Davajan V, Kletzky 0, March CM, Roy S, Mishell DR Jr: The significance of galactorrhea in patients with normal menses, oligomenorrhea, and secondary amenorrhea. Am J Obstet Gynecol 130:894, 1978 125. Sherman BM, Harris CE, Schlechte J, Duello TM, Halmi NS, Van Gilder J, Chapler FK, Granner DK: Pathogenesis of prolactin screening pituitary adenomas. Lancet 2:1019, 1978 126. March CM, Kletzky OA, Israel R, Davajan V, Mishell DR: Amenorrhea, galactorrhea and piotuitary tumors: postpill and non-postpill. Fertil Steril 28:346, 1977 127. Van Campenhout J, Blanchet P, Hugues B, Papas S: Amenorrhea following the use of oral contraceptives. Fertil Steril 28:728, 1977 128. March CM, Mishell DR, Kletzky OA, Israel R, Davajan V, Nakamura RM: Galactorrhea and pituitary tumors in postpill and non-postpill secondary amenorrhea (pituitary tumors in secondary amenorrhea). Am J Obstet Gynecol 134:45, 1979 129. Costello RT: Subclinical adenoma of the pituitary gland. Am J Pathol 12:205, 1936 130. Coulam CB, Annegers JF, Abboud CF, Laws ER Jr, Kurland LT: Pituitary adenoma and oral contraceptives: a case-control study. Fertil Steril 31:25, 1979 13l. Gusberg SB, Kaplan AL: Precursors of corpus cancer. Adenomatous hyperplasia as stage 0 carcinoma of the endometrium. Am J Obstet Gynecol 87:662, 1963 132. Gusberg SB, Moore DB, Martin F: Precursors of corpus cancer. 2. A clinical and pathological study of adenomatous hyperplasia. Am J Obstet Gynecol 68:1472, 1954

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133. Lucas WE: Causal relationships between endocrinemetabolic variables in patients with endometrial carcinoma. Obstet Gynecol Survey 29:507,1974 134. Bromberg YM, Libane E, Laufera A: Early endometrial carcinoma following prolonged estrogen administration in an ovariectomized woman. Obstet Gynecol 14:221, 1959 135. Fremont-Smith M, Meigs JV, Gramham RM, Gilbert HH: Cancer of endometrium and prolonged estrogen therapy. JAMA 131:805, 1946 136. Sommers SC: Carcinoma of the endometrium. In The Uterus, Edited NJ Norris, AT Hertig, MR Abell. Baltimore, Williams & Wilkins Co, 1973, p 277 137. Gusberg SB, Kardon P: Proliferative endometrial response to theca-granulosa cell tumors. Am J Obstet Gynecol 111:633, 1971 138. Fechner RE, Kaufman RH: Endometrial adenocarcinoma. Cancer 34:444, 1974 139. Gusberg SB: Precursors of corpus carcinoma, estrogens, and adenomatous hyperplasia. Am J Obstet Gynecol 54:905, 1947 140. Mack TM, Pike MC, Henderson BE, Pfeffer RI, Gerkins VR, Aurthur M, Brown SE: Estrogens and endometrial cancer in a retirement community. N Engl J Med 294: 1262, 1976 141. Gray LA, Christopherson WM, Hoover RN: Estrogens and endometrial carcinoma. Obstet Gynecol 49:385, 1977 142. Smith DC, Prentice R, Thompson DJ, Herrmann WL: Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293:1164, 1975 143. Zeil HK, Finkle WD: Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293:1167, 1975 144. McDonald TW, Annegers JF, O'Fallon WM, Dockerty MB, Malkasian GD Jr, Kurkland LT: Exogenous estrogen and endometrial carcinoma: case-control and incidence study. Am J Obstet Gynecol 127:572, 1977 145. Antunes CMF, Stolley PD, Rosenshein NB, Davies JL, Tonascia JA, Brown C, Burnett L, Rutledge A, Pokempner M, Garcia R: Endometrial cancer and estrogen use. N Engl J Med 300:9, 1979 146. Garcia CR, Goldzieher JW, Massey JB: Oral contraceptives in human reproduction, conception and contraception, Edited by ESE Hafez, TN Evans. Hagerstown Md, Harper and Row, 1973, p 335 147. Goldzieher JW, Martinez-Manatow J, Livingston NB, Moses LE, Rice-Wray E: The use of sequestial estrogen and progestin to inhibit fertility. West J Surg 71:187, 1963 148. Silverberg SG, Makowski EL: Endometrial carcinoma in young women taking oral contraceptives. Obstet Gynecol 46:503, 1975 149. Lyon FA: The development of the endometrium in young women receiving long-term sequential oral contraception: Report of four cases. Am J Obstet Gynecol 123:299, 1975 150. Silverberg SG, Makowski EL, Roche WD: Endometrial carcinoma in women under 40 years of age: comparison of cases in oral contraceptive users and non-users. Cancer 29:592, 1977 15l. Lyon FA, Frisch MJ: Endometrial abnormalities occurring in young women on long-term sequential oral contraception. Obstet Gynecol 47:636, 1976 152. Cohen CJ, Deppe G: Endometrial carcinoma and oral contraceptive agents. Obstet Gynecol 49:390, 1977

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153. Kelley HW, Miles PA, Buster JE, Scragg WH: Adenocarcinoma of the endometrium in women taking sequential oral contraceptives. Obstet Gynecol 47:200, 1976 154. Kreutner A Jr, Johnson D, Williamson MO: Histology of the endometrium in long-term use of a sequential oral contraceptive. Fertil Steril 27:905, 1976 155. Anonymous: Sequential oral contraceptives removed from the market. FDA Drug Bull 6:26, 1976 156. Tseng L, Gurpide E: Effect of estrone and progesterone on the nuclear uptake of estradiol by slices of human endometrium. Endocrinology 93:245, 1973 157. Tseng L, Gurpide E: Effects of progestins on estradiol receptor levels in human endometrium. J Clin Endocrinol Metab 41:402, 1975 158. Ravenholt RL: Malignant cellular evolution: an analysis of the causation and prevention of cancer. Lancet 1:523, 1966 159. Kistner RW: The effects of progestational agents on hyperplasia and carcinoma in situ of the endometrium: a 10 year follow-up. Int J Gynecol Obstet 8:561, 1970 160. Czernobilsky B, Garcia CR, Wallach EE: Endometrial histology and parenteral estrogen-progestogen administration. Fertil Steril 20:75, 1969 161. Flowers CE: Effects of new low dosage form of norethynodrel-mestranol. Clinical evaluation and endometrial biopsy study. JAMA 188:1115, 1964 162. Wentz WB: Progestin therapy in endometrial hyperplasia. Gynecol Oncol 2:362, 1974 163. Kistner RW: The effects of progestational agents on hyperplasia and carcinoma in situ of the endometrium. Int J Obstet Gynecol 8:561, 1970 164. Ferenczy A: How progestogens effect endometrial hyperplasia and neoplasia. Contemp Ob/Gyn 11:137, 1978 165. Green TH: Leiomyomas, adenomyosis and other benign diseases ofthe uterus. In Gynecology: Essentials ofClinical Practice, Third Edition. Boston, Little, Brown and Co, 1977, p 381 166. Martin CE: Marital and coital factors in cervical cancer. Am J Public Health 57:803, 1967 167. Rotkin ID: A comparison review of key epidemiological studies in cervical cancer related to current searches for transmissible agents. Cancer Res 33:1353, 1973 168. Merritt CG, Rosenberg SH, Edington B, Losciuto LA: Age at first coitus and choice of contraceptive method: preliminary report on a study of factors related to cervical neoplasia. Soc BioI 22:255, 1975 169. Miller DF: The impact of hormonal contraceptive therapy on a community and effects on cytopathology of the cervix. Am J Obstet Gynecol 115:978, 1973 170. Worth AJ, Boyes DA: A case control study into the possible effects of birth control pills on pre-clinical carcinoma of the cervix. J Obstet Gynaecol Br Commonw 79:673, 1972 171. Melamed MR, Koss LG, Flehinger BJ, Kelisky RP, Dubrow H: Prevalence rates of uterine cervical carcinoma in situ for women using the diaphragm or contraceptive oral steroids. Br Med J 3:195, 1969 172. Amstey MS: Genital herpes virus and cervical carcinoma. Con temp Ob/Gyn 3:99, 1977 173. Adelvsi B, Osunkoya BO, Fabiyi A: Herpes type-2 virus antigens in human cervical carcinoma. Obstet Gynecol 47:545, 1976 174. Tobin SM, Wilson WD, Papsin FR: Relation of herpes

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virus hominis type II to carcinoma of the cervix. Obstet Gynecol 51:707, 1978 Gall SA, Bourgeois CH, Maguire R: The morphological effects of oral contraceptive agents on the cervix. JAMA 207:2243, 1969 Wilkinson E, Dufour DR: Pathogenesis of microglandular hyperplasia of the cervix uteri. Obstet Gynecol 47:189, 1976 Coppelson M, Reid B: A colposcopic study of the cervix during pregnancy and the puerperium. J Obstet Gynaecol Br Commonw 73:575, 1966 Fluhmann CF: Histology. In The Cervix Uteri and Its Diseases, Edited by CF Fluhmann. Philadelphia, WB Saunders Co, 1961, p 46 Coppelson M, Reid B: Origin of premalignant lesions of cervix uteri. Prog Gynecol 6:517, 1975 Candy J, Abell MR: Progestogen-induced adenomatous hyperplasia of the uterine cervix. JAMA 203:85, 1968 Payan HM: Atypical endocervical hyperplasia and oral contraceptives: report of a case. Michigan Med 70:609, 1971 Graham J, Graham R, Hirabayashi K: Reversible "cancer" and the contraceptive pill. Obstet Gynecol 31:190, 1968 Anderson WR, Levine AJ: The contraceptive polyp: a diagnostic dilemma. J Iowa Med Soc 58:585, 1968 Taylor HB, Irey NS, Norris HJ: Atypical endocervical hyperplasia in women taking oral contraceptives. JAMA 202:185, 1967 Thomas DB: Relationship of oral contraceptives to cervical carcinogenesis. Obstet Gynecol 40:508, 1972 Miller DF: The impact of hormonal contraceptive therapy on a community and effects on cytopathology ofthe cervix. Am J Obstet Gynecol 115:978, 1973 Boyce JG, Lu T, Nelson JH, Furchter RG: Oral contraceptives and cervical carcinoma. Am J Obstet Gynecol 128:761, 1977 Malamed MR, Flehinger BJ: Early incidence rates of precancerous cervical lesions in women using oral contraceptives. Gynecol Oncol 1:290, 1973 Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW: Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 124:573, 1976 Ory HW, Conger SB, Naib Z, Tyler CW, Hatcher RA: Preliminary analysis of oral contraceptive use and risk of developing premalignant lesions of the uterine cervix. In Pharmacology of Steroid Drugs, Edited by S Garrantini, HW Berendes. New York, Raven Press, 1977 Stern E, Forsythe AB, Coffelt CF: Steroid contraceptive use and cervical dysplasia; increased risk of progression. Science 196:1460, 1977 Ory H: Functional ovarian cysts and oral contraceptives: negative association confirmed surgically: a cooperative study. JAMA 228:68, 1974 Ylukorkala 0: Ovarian cysts and hormonal contraception. Lancet 2:1101, 1977 Lingeman CH: Etiology of cancer of the human ovary, a review. J Natl Cancer Inst 53:1603, 1974 Newhouse ML, Pearson RM, Fullerton JM, Boesen EAM, Shannon HS: A case control study of carcinoma of the ovary. Br J Preventive Soc Med 31:148, 1977 Stone M, Dent J, Kardana A, Bagshawe KD: Relationship of oral contraception to the development of trophoblastic tumour after evacuation of a hydatidiform mole. Br J Obstet Gynaecol 83:913, 1976

Received April 3, 1979. Reprint requests: George R. Huggins, M.D., Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pa. 19104.