Oral contraceptives and neoplasia: 1987 update

Transcription

1 FERTILITY AND STERILITY Copyright (; 1987 The American Fertility Society Vol. 47, No. 5, May 1987 Printed in U.SA. Oral contraceptives and neoplasia: 1987 update George R. Huggins, M.D. Peter K. Zucker, M.D. The Johns Hopkins University School of Medicine, Baltimore, Maryland Combined estrogen-progestogen oral contraceptives (OCs) have been available in the United States since The first compound approved contained 10 mg norethynodrel and 150 J.Lg mestranol. Current worldwide use is approximated at 55 million 1 women and United States use at 8 to 10 million women. 2 Clearly, for justification of such wide use of potent drugs, the risk-benefit ratio must weigh substantially in favor of the drug benefits. In the past 26 years more than 40 brands of combined OCs 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). Most women are now using combined OCs with 0.3 to 1 mg progestogen and 20 to 50 J.Lg estrogen. Since 1970 all of the newly introduced compounds have used ethinyl estradiol (EE 2 ) as the estrogen fraction. The progestogens present in the low-dose and triphasic pills are ethynodiol diacetate, norethindrone, norethindrone acetate, and norgestrel. 1 Outside the United States some of the 17a-hydroxyprogesterone derivatives are in use. 1 However, these derivatives were withdrawn from the United States market in response to concerns regarding the occurrence of neoplastic lesions in dogs.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 OC 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.3 Other serious side effects such as cardiovascular problems with use of OCs and severe pelvic infections with use of intrauterine devices (IUDs) have extensive documentation. Morbidity and mortality rates have been estimated 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 OCs and human neoplasia in light of pregnancy risk or benefit for oral contraception. Our first review of this subject was published in The current discussion will serve as an update to that original presentation. In the past 6 years numerous new data have been published regarding the relationship between OCs and neoplasia that has helped clarify relationships. The most salutary findings have been the protective effect of OCs on endometrial and ovarian cancer. The most disturbing has been the growing consensus regarding an adverse effect on cervical neoplasia. The more recent epidemiologic studies have been. much better able to assess confounding variables and as such appear to have more validity than the older studies. 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 after exposure to a carcinogen, until the development of overt malignancy7; (3) there is a low incidence of malignant Vol. 47, No. 5, May 1987 Huggins and Zucker OCs and neoplasia 733

2 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 before human investigative use. These animal studies provide only presumptive evidence of carcinogenic potential within a single species and sometimes within a single strain of that species. 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 degree of certainty in relation to the human being. 3 The reader is referred to the George Washington University Center Population Reports,S 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 section. The relationship of OCs 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 human beings include various epidemiologic approaches 9 (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 itself 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 that is confirmed by these multiple approaches. 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. 10 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. ll reported the occurrence of benign liver tumors in OC users. These initial reports provided the impetus for retrospective case-con- Table 1. Four Epidemiologic Methods Used in Studying OCs and Neoplasms a Case reports Method Disease rate trends Case comparison 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 Compare exposure to environmental factor in groups with a disease with that in similar groups without the disease Compare disease incidence in groups exposed to an environmental factor with that in groups not exposed Functions Often the source of first suspicions about disease causes; encourage more rigorous study Can be co~pared with trends in exposure to environmental factors; help assess impact of disease on public health Determine relative difference in exposure between those with and those without a disease; appropriate when the disease is rare or quick results are desired Appropriate when fullest information, least subject to unavoidable possibilities of methodologic bias, is required or when information on more than one disease is sought amodified from Population Reports: Oral contraceptives: update on usage, safety, and side effects.9 Limitations Few conclusions are made on the basis of case reports alone For detectable changes in rates, exposure to environmental factor must be widespread in the population and must alter the chances of development of the disease Do not determine the incidence rate in participants, which may be faulty Often require study of large groups over long periods of time, especially with rare diseases 734 Huggins and Zucker OCs and neoplasia Fertility and Sterility

3 trol 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. No conclusions regarding either the incidence of disease or risk of development of 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. 12 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 development or progression of cancer. It will, however, monitor dramatic changes such as those that have taken place with regard to the increasing incidence of carcinoma of the lung in women. 13 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 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 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 ensuring that the populations studied are as similar as possible. The use of OCs 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 on the ratio between the incidence of OC use 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 implies a negative association, and> 1 a positive association with exposure to OCs. 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 5/1000 has more important implications than five times relative risk in a disease with a baseline incidence of 511,000,000. 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 that are able to obtain necessary numbers of patients with rare or lowincidence disease. COHORT STUDIES 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 OCs requires large numbers of patients followed over a long period of time in order to gather enough information for adequate statistical analysis 20 (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 ade- Table 2. Reported Annual Incidence of Cancers of Selected Sites/lOO,OOO Women in Selected Countries, 1960s and 1970s a Site of cancer Nigeria United States Country Israel India Japan Breast Uterine cervix Uterine corpus Ovaryb amodified from Waterhouse et au2 blncludes tube. Vol. 47, No.5, May 1987 Huggins and Zucker OCs and neoplasia 735

4 1 Table 3. Minimal Samples Required to Detect Differences in Disease Rates Between DC Users and Controls in Prospective Stud~ Persons reo Annual inci quired in Site of No. of years dence rate each group: cancer after onset in con incidence 2 of study trols/lo,ooo times in OC users Breast ,000 Corpus ,000 uteri Cervix ,000 Breast ,000 Corpus ,000 uteri Cervix ,000 UModified from Seigel and Corfman. 20 quately conducting a contraceptive cohort study have limited their number. At present there are only two large contraceptive cohort studies in progress-both in the United Kingdom. The Royal College of General Practitioners (RCGP) enrolled 23,611 current OC users and 22,766 nonusers during 1968 to 1969,21 and Vessey et al.22 enrolled 9653 OC users and 7379 nonusers during 1968 to 1974 in the Oxford Family Planning Association (OFPA) study. Care must be taken not to extrapolate data to other (dissimilar) populations. For instance, subjects in the population of the OFPA study22 were white, married, economically middle class, and 25 to 39 years of age 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. stronger in families with several relatives involved, especially if the disease has been premenopausal and bilateral. 34 The strongly positive relationship with benign breast disease or precancerous mastopathy is most important because of the high incidence of benign breast disease in the general population and the considerable difficulty in defining which type of benign breast neoplas1' a IS. " precancerous.,,35 NIl' u Iparous women or women who postpone the birth of a first child until after age 34 also show increased risk. 24 BREAST CANCER, PRECLINICAL PHASE The duration of preclinical or predetected breast cancer may extend over many years. Gullino36 has estimated this "latent" time on the basis of an assumed 100 days' doubling time for breast cancer cells (Fig. 1). In 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 has support from the studies of Spratt and Spratt,37 Collins et al.,3s and Silvestrimi et al.39 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 OC steroids one possible. effect would be the appearance of ' the OCs AND BREAST DISEASE RISK FACTORS IN CARCINOMA OF THE BREAST Several major risk factors for carcinoma of the breast have been identified (Table 4). The marked predisposition for this disease in the woman is attributed largely to the endocrine influence of estrogen on breast tissue. Breast cancer has occasionally been reported in men treated with long-term exogenous estrogen for carcinoma of the prostate25 or in male-to-female transsexuals receiving supplemental estrogen.26 Studies of postmenopausal estrogen use have yielded conflicting conclusions. Several studies have shown an increased risk of breast cancer associated with estrogen use,27-29 whereas others have shown none The genetic predisposition is 736 Huggins and Zucker DCs and neoplasia Table 4. Major Risk Factors in Breast Cance~ Risk factor Comparison Ratio Sex Female Male 99/1 Age > 40 < 40 85%/15% Genetic predisposition; Yes No 3/1 family history of breast cancer Mother and sister; Yes No 9/1 bilateral and premenopausal Previous benign breast Yes No 3/1 disease Precancerous mastopathy Yes No 5/1 Previous cancer of Yes No 5/1 one breast Parity (reflects early Nullip- Parous 3/1 first parity) arous Age at first birth Late Early 4/1 (> 34) (18) Lactation Yes No 111 umodified from Leis. 24 Fertility and Sterility

5 ~... 10" CJ... '" 10' 0 a: 10' '" 10' ~ ::> 10' z 100 DAYS DOUBLING TIME Dieme,., em , YEARS OF GROWTH Pr.m.mmogr.phlc t lmm NUMBER OF CELL DOUBLINGS Figure 1 Estimation of duration of preclinical or predetected breast cancer. Reproduced from Gullino 36 with permission. 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. BREAST CANCER AND CHRONIC MASTITIS Benign breast disease is not a single well-defined 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. 4o This inconsistency makes it difficult to compare accurately conclusions from various reports. McDivitt et a1. 41 have shown a much higher risk of cancer associated with lesions having more marked degrees of atypia. Black and Chabon 42 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 (five times) for development of cancer was shown in atypia grades 3 and 4 as compared with grades 1 and 2. Kodlin et a1. 40 studied 2931 women with at least one benign breast biopsy obtained at the Kaiser-Permanente Medical Center in Oakland, CA, between 1948 and 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 person-year rate. According to the Black-Chabon atypia scoring sys- 40 tern, the risk increased steadily from 2.5 for lesions classified as types 1 and 2 to 21.1 for type 5. Kodlin et a1. 40 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... " Cole 43 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. Few epidemiologic studies before 1975 that investigated risk of breast cancer and benign breast lesions categorized lesions on the basis of pathologic examination of benign breast tissue. A consensus conference jointly sponsored by the College of American Pathologists and the American Cancer Society convened in 1985 to determine the risk relationship between benign lesions and breast cancer. Risks were determined and categorized by pathologic examination 44 (Table 5). The most common symptomatic benign breast conditions are lobular hyperplasia, cystic duct dilation, fibroadenoma, and sclerosing adenosis. These are associated with no increased risk of breast cancer. Only those patients with significant hyperplasia show increased risk of breast cancer (1.5 to 5 times). This classification may help to define more clearly subgroups of patients with benign breast disease. Future epidemiologic studies will need to define better patients with "benign breast disease." Table 5. Relative Risk for Invasive Breast Carcinoma on the Basis of Pathologic Examination of Benign Breast Tissue a Adenosis, sclerosing or florid Apocrine metaplasia Cysts, macro and/or micro Duct ectasis No increased riskb Fibroadenoma Fibrosis Hyperplasia, mild (> 2 but < 4 epithelial cells in depth) Slightly increased risk (1.5 to 2 times)b Hyperplasia, moderate or florid, solid or papillary Papilloma with fibrovascular core Moderately increased risk (5 times)b Atypical hyperplasia (borderline lesion) Ductal Lobular Mastitis (inflammation) Periductal mastitis Squamous metaplasia amodified from the College of American Pathologists. 44 bfor invasive breast carcinoma among women with lesions specified relative to comparable women who have had no breast biopsy. Vol. 47, No.5, May 1987 Huggins and Zucker OCs and neoplasia 737

6 OCs AND BENIGN BREAST DISEASE Before 1979 the relationship of combined OCs to benign breast disease was consistently favorable. Most studies21, 22, 35, have shown OC use to be associated with significantly decreased risk of benign breast neoplasia. In spite of the nearly unanimous agreement that OCs exert a protective effect with relation to benign breast disease, a number of questions and problems persist: (1) Does response differ with respect to duration of use? (2) Does response differ according to histologic cell type? (3) Does response differ for various types and dosages of contraceptive steroids? DURATION OF USE Most studies21, 22, have documented with increasing length of OC use a decrease risk that begins to appear after 2 years and persists for more than 4 years of use. There is no suggestion in these studies that the risk increases with longer use. There is some disagreement as to persistence of this protective effect after use of OCs is stopped. Although Ory et al.45 and Fasal and Paffenbarger47 have shown some persistence of a protective effect, this finding is not confirmed by most other studies. RESPONSE BY HISTOLOGIC CELL TYPE Most studies showing diminished risks for development of benign breast neoplasia during OC use have not analyzed lesions by histologic type. The studies that have examined fibrocystic disease and fibroadenoma separately have reported somewhat inconsistent results. Ory et al.45 reported decreased risks for both fibrocystic disease and fibroadenoma with combined pills. Sartwell et al.48 found the decreased risk to hold true only for fibrocystic disease with combined pills. Brinton et al.49 analyzed the experience in the OFPA Contraceptive study through This particular study separated the types of benign breast disease into four separate categories: fibroadenoma, chronic cystic disease, nonbiopsied breast lumps, and other benign breast disease. The protective effect was consistent for all categories. Furthermore each category showed significant trends of decreasing risks with increasing years of use (Table 6). The reductions in risk for current users were 84% for fibroadenoma, 53% for chronic cystic disease, 48% for nonbiopsied breast lumps, and 40% for other breast disease. Women who had discontinued pill use 1 or more years before diagnosis demonstrated no reduction in risk. Livosli et al.,50 using a case-control study, investigated the risk of development of fibrocystic disease in OC users by applying the Black-Chabon scoring system. The main purpose of this study was to determine whether the association between OC use and fibrocystic disease varied according to the extent of the breast epithelial atypia. Two hundred five premenopausal women aged 20 to 44 years with a diagnosis of fibrocystic disease, admitted to two hospitals in New Haven, CT, constituted the case population. These patients were matched individually with surgical patients for age, marital status, race, and education. All biopsies were separately classified according to the pathologic criteria of Black-Chabon.42 The odds ratio for fibrocystic disease among women who ever used OCs was determined according to the average ductal-atypia score. These Table 6. Relative Risks orbenign Breast Disease by Use orocs; OFPA Contraceptive Study, United Kingdom, a Measure of exposure Ever-use No Yes 95% confidence interval Years of use Never used < x 1 for linear trend amodified from Brinton et al. 49 Fibroadenoma (n = 74) ( ) Chronic cystic disease (n = 211) ( ) Nonbiopsied breast lumps (n = 331) ( ) Other breast disease (n = 70) ( ) Huggins and Zucker OCs and neoplasia Fertility and Sterility

7 determinations were carried out for "ever-users" and for "4-year duration users" compared with patients who had never used OCs. The odds ratio for mild degrees of ductal atypia was less than 1 for both "ever-users" and "4-year users." The odds ratio was 3 for "ever-users" and 3.2 for "4-year users" in patients who had severe ductal atypia. Thus the decreased frequency of fibrocystic disease applied only to those forms of the disease in which epithelial atypia was minimal or absent. Women with marked atypia showed no difference in frequency among long-term users as compared with "never users." Livosli et al.50 believe that long-term use of OCs protects only against the forms of fibrocystic disease that are not firmly associated with an increased risk of cancer but not against the premalignant forms of breast atypia. There was no suggestion that the use of OCs was associated with a higher incidence of the more advanced grades of atypia. PROGESTOGEN EFFECT The women subjects in both the RCGp21 and the Brinton49 studies were taking compounds that all contained 50 mg EE2. The progestogen dosages varied from 1 to 4 mg. The protective effect was significantly greater in the high-progestogen pills (relative risk, 0.27). There was virtually no protective effect (relative risk, 0.8) among the 1-mg progestogen pills. Berkowitz et al. in provided additional support for the lack of protective effect among women taking low-progestogen-dose pills. This case-control study examined 633 women with biopsy-proved fibrocystic breast disease and 1062 controls from five Connecticut hospitals. For premenopausal women there was no evidence that long-term use of OCs was associated with a decreased risk of fibrocystic breast disease among either current or past users. In an analysis of compounds most frequently used in the United States, estrogen (20 to 50 f-lg) and progestogens (1 to 2.5 mg) showed relative risks of 0.95 to 1.77, respectively, which are not indicative of a protective effect. Additional studies are needed to clarify these findings further. Ory et al.2 estimated that the protective effect of OCs on benign breast disease among the 8,000,000 United States women using OCs results each year in 23,490 fewer breast biopsies. These figures were calculated from estimates of the protective effect of pre-1979 studies. Vol. 47, No.5, May 1987 Should the conclusions of Berkowitz et al.51 and Brinton et al.49 be confirmed, the public health benefit of OCs on benign breast neoplasia may be much less than current estimates. OCs AND BREAST CANCER Benign breast disease represents a significant risk factor for the ultimate development of carcinoma of the breast. The early studies that show a consistently protective effect on benign disease do not show the same protective effect for breast cancer (Table 7).21,22,45,47,52-55 Most of the derived risk ratios are close to unity. This figure can be interpreted to indicate no evidence of either positive or negative association between breast cancer and up to 4 years' use ofocs. In a recent review Clavel et al. 56 surveyed 22 major epidemiologic studies that investigated the relationship between OC use and breast cancer. Three cohort studies were analyzed: RCGP study, the OFPA Contraceptive study, and the Walnut Creek Contraceptive Drug study. The only subgroup whose risk reached statistical significance was among young women in the RCGP study (Table 8). Among the 18 case-control studies the overall adjusted relative risk among OC users as compared with nonusers was significantly> 1 in only one study (Clavel et al.57). However, there are suggestions that certain subgroups of women may be at increased risk for breast cancer from OC use.47, 58 The 1975 case-control study by Fasal and Paffenbarger47 in which past and current OC usage in 452 premenopausal women with breast cancer was analyzed shows a paradoxical risk pattern. A significantly higher relative risk was found among the cancer patients who had used OCs for 2 to 4 years. However, the risk was not increased Table 7. OCs and Breast Cancer: Literature Review Report Type of study Rate ratio Arthes et al. 52 Case-control 0.7 Boston Collaborative Case-control 0.6 Drug Surveillance program53 Fasal and patrenbarger47 Case-control 1.1 Kelsey et al. 54 Case-control 1.35 Vessey et al. 55 Case-control 0.8 Ory et al.45 Cohort 0.7 Royal College of General Cohort 1.1 Practitioners21 Vessey et al. 22 Cohort 0.4 Huggins and Zucker OCs and neoplasia 739

8 Table 8. Age-Standardized Risk Ratios of Breast Cancer Among OC Users and Nonusers a All women Never-users 1.00 (39) Current users 1.26 (50) Ex-users 1.14 (45) RCGP Women aged C (8) 2.81 c,d (24) amodified from Clavel et a1. 56 blncidence rates x 10 5 in parentheses. calso standardized for parity at diagnosis, smoking habit, and social class. dp < 5%. eratio of incidence rates of OC users versus nonusers. OFPA Walnut Creek All women Women aged study 21hJ (52) 1.00 (28) 1.00 (114) 1.04e (54) 0.64e (18) 1.2 (131) 0.87e (45) 0.54e (15) for those patients who had taken pills for < 2 years of for 4 to 8 years. The authors proposed two possible conclusions: (1) "that the findings were due simply to chance" or (2) "that oral contraceptives accelerate the growth rate of pre-existing subclinical malignant lesions, with these lesions reaching the level of clinical recognition only after 2 years of drug usage and all being diagnosed within 2 additional years." A second group with increased risk were those patients who had a history of prior breast biopsy and OC usage for 6 or more years. There was no reported analysis of these prior biopsy specimens for degree of atypia or specific cell types. Pike et al. 58 conducted a case-control study in Los Angeles in There were 314 women with breast cancer and 314 individually matched controls. He concluded that women < 37 years of age who had used high-progestin OCs before age 25 were at increased risk for breast cancer. He found a steadily increasing risk according to duration of use for all OCs. The relative risk for those women who used high-progestin OCs was further increased (Table 9). Two studies58, 59 showed a significance in risk among women who began OC use before age 25. Pike et a1. 58 performed the only study that showed a significant linear trend with longer duration of use before age 25. None of the studies that examined risks by years since initial use or by years since last use Table 9. Relative Breast Cancer Risk a Months of OC use o > 73 Any use amodified from Pike et a1. 58 High progestin Huggins and Zucker OCs and neoplasia 00 found a significant increase in any group. Four studies found some increased risk with OC use before first full-term pregnancy However there was no significant association among nulliparous women. The type and dosage of hormone have not been correlated with risk except for the study of Pike et al.,58 in which the high-progestogen potency pills were found to carry greater risk. Pike's classification of progestogen potency has been widely questioned. Paul et al.64 in 1986 conducted a national population-based case-control study of 433 New Zealand women aged 25 to 54 with newly diagnosed breast cancer compared with 897 control women. Analysis of risk by duration of use, age at first use, and time since first use showed no increased risk. Moreover, even women starting pill use before age 20, who had taken pills more than 15 years previously and had continued to use them for more than 10 years, were not at an increased risk. The authors felt that the statistical power of their study was high because of exceptionally high pill use by New Zealand women. In 1975 the prevalence of pill use was reported to be higher in New Zealand than any other country except Holland.8 The largest ongoing United States study designed to evaluate the risks of steroid use and multiple female cancers is the Cancer and Steroid Hormone study of the Centers for Disease Control and the National Institute of Child Health and Human Development.65 Because of the repeated references to portions of this study, the methods of this investigation will be described in detail. The Cancer and Steroid Hormone study-a multicenter population-based, case-control study-is coordinated by the Division of Reproductive Health, Center for Health Promotion and Education, the Centers for Disease Control, with support from the Center for Population Research of the National Institute of Child Health and Hu- Fertility and Sterility

9 man Development and the National Cancer Institute (NCI). Enrollment of subjects was begun in December 1980 through the Surveillance, Epidemiology, and End Results (SEER) Centers for the NCI in eight areas (the metropolitan areas of Atlanta, Detroit, San Francisco, and Seattle; the states of Connecticut, Iowa, and New Mexico; and the four urban counties of Utah). CASES The case study subjects were women 20 to 54 years of age with histologically confirmed primary breast cancer newly diagnosed between December 1, 1980, and December 31, 1982, who resided in one of the eight SEER reporting areas. A case group of 4711 women was available for analysis. CONTROLS Controls were women selected according to Waksberg's method of random-digit dialing66 in the geographic areas of the cases. Each month, an appropriate proportion of potential controls in each 5-year age group was selected to match the age distribution of women with breast cancer. A control group of 4676 women was available for analysis. INTERVIEW Each study participant was interviewed in person according to a pretested standardized questionnaire. The questionnaire focused on reproductive, contraceptive, and family histories of cancer; use of medical services; and personal characteristics and habits. To asist in recall of the use of OCs and other noncontraceptive hormone therapy, two memory aids were used: a book of photographs of all OC preparations marketed in the United States since 1960, and a calendar on which to record major life events around which contraceptive use might be better remembered. ANALYSIS Odds ratios as estimates of the relative risk were calculated according to the method of Mantel and Haenszel,67 and 95% confidence intervals according to Miettinen's test-bases method.68 Logistic regression69 was used to control simultaneously for several variables considered a priority to be potential confounders of the results; vari- Vol. 47, No.5, May 1987 abies included in the model were age, menopausal status, age at first term pregnancy, family history of breast cancer, area of residence, and history of benign breast disease before first use of OCs. The results of this logistic regression analysis agreed closely with results from the Mantel-Haenszel procedure67 to adjust for each of 25 potentially confounding variables individually. Cases were 4711 women 20 to 54 years of age with newly diagnosed breast cancer selected from eight population-based cancer registries. Controls were 4676 women selected by random-digit dialing in the same population area. The relative risk of breast cancer among women who had ever used OCs compared with women who had never used them was 1.0. There was no increased risk among long-term users (15 or more years of use) and no increased risk with increase in time since last use. The risk of breast cancer was not significantly different among users of different types of OCs. Analysis was done on women who used either sequential, progestin only, two or more compound, or an unidentified type of OC. Use before first term pregnancy, menopausal status or family history of breast cancer, and history of surgery for benign breast disease did not show increased risk. Those using only mestranol or only EE2 as the estrogen component showed no increased risk, and there was no significant increased risk by use of any specific progestin contained in combination OC. No consistent pattern of association between OC use and breast cancer is apparent from the many studies conducted in the past 10 years. Unlike the studies involving ovarian, endometrial, and cervical neoplasia, refinement in study design has not produced consistent findings. These inconsistent findings argue strongly against a significant association between OC use and the risk of breast cancer. Some recent studies continue to raise concern over certain subgroups of women (i.e., nulliparous women and women who began pill use younger than 25). Further studies on these specific populations are necessary. CERVICAL NEOPLASIA The epidemiologic factors responsible for the development of cervical dysplasia and subsequent progression to carcinoma in some patients are complex and poorly understood. One of the major epidemiologic factors in carcinoma of the cervix seems to be young age at first intercourse. Others, Huggins and Zucker oes and neoplasia 741

10 such as human papilloma virus, multiparity, high frequency of intercourse, multiple partners, and low socioeconomic status, may also relate to early age at the time of first intercourse Conclusions derived from a number of epidemiologic studies of cervical neoplasia vary considerably. A number of factors contribute to this variability: (1) The histologic interpretation of degrees of dysplasia and carcinoma in situ may vary from one pathologist to another. (2) The most important risk factors (age at first intercourse, frequency of intercourse, and number of sexual partners) are difficult to determine accurately. In spite of the large numbers of both case-control and cohort studies, only one study before 1975 specifically analyzed the issues of age at first intercourse and contraceptive choice.72 (3) There is a tendency for women using steroidal contraception to avail themselves of medical care more frequently than noncontraceptive users. As a result, certain disease processes may be underreported in populations not using contraceptives. (4) Results are inconsistent in quantitating relative risks. Some reports conclude that there are "remarkable similarities between the test and control group in each age bracket" 73 or "no significant differences in occurrences or duration of use.,,74 (5) Some reports concern "prevalence rates," which may include patients with disease at the time they enter the study.75 (6) There is a confounding influence of sexually transmitted carcinogens. The carcinogenic effects of human papilloma virus and herpes type II are most important risk factors for this disease.76, 77 Epidemiologic studies must be designed to detect the incidence of these diseases in their cases and controls. Analysis must also control adequately for these factors. Unfortunately, the authors of the most recent sophisticated case-control studies of OC use and risk of cervical cancer have not been able to accomplish these ends. There are major problems in obtaining an accurate history of specific sexually transmitted diseases. Many patients cannot or will not relate a history of a specific sexually transmitted disease. Condom and diaphragm use may exert some barrier protective effect against these agents. Comparisons between incidence rates of infection and cervical neoplasia in diaphragm users versus OC users may show a protective effect of diaphragm use rather than an increased rate with OC use. 742 Huggins and Zucker Des and neoplasia The 1969 study by Melamed et al. 75 illustrates well some methodologic problems with epidemiologic studies conducted during the 1960s and early 1970s. They surveyed the incidence of cervical carcinoma in situ and a "matched" population of Planned Parenthood patients in New York City. Five factors were considered in the study design for collection of clinical data: age, ethnic origin, age at first pregnancy, number of children born alive, and net weekly family income. No attempt was made to determine age at first coitus, frequency of coitus, or number of different sexual partners and marital status. Analysis of the "matched populations" of OC choosers and those who selected the diaphragm revealed significant differences in race, income, and age at first pregnancy. The diaphragm users were predominantly white, of upper-income socioeconomic status, and more likely to have had their first pregnancy after age 20. The OC choosers were predominantly black or Puerto Rican, of lower-income socioeconomic status, and more likely to have had their first pregnancy before the age of 20. Prevalence rates were determined for patients choosing OCs (27,508) and patients selecting the diaphragm (6809). The prevalence rate for carcinoma in situ for OC choosers was 6.6/1000 and 3.8/1000 for diaphragm users. This difference was small but statistically significant. Assuming that this was not a low-probability statistical variation, three possible explanations were offered: (1) a protective effect of the diaphragm acting as a barrier, (2) a causal effect of steroids acting on the cervicovaginal epithelium, and (3) some unknown factor(s) in the makeup, behavior, or habits of a woman that would alter her probability of development of cervical carcinoma and at the same time impel her to choose a particular contraceptive. It is important to appreciate that the study by Melamed et al.75 demonstrated only a tendency of patients with carcinoma in situ to choose OCs more frequently than the diaphragm. No conclusions could be drawn regarding the development of carcinoma in situ in patients using OCs. Ory et al. in determined the prevalence rates for cervical dysplasia and carcinoma in situ for 15,477 OC users and 6663 IUD users at the Grady Hospital Family Planning Clinic in Atlanta. This study was designed in part to answer the question raised by the study by Melamed et al.,75 namely, does the prevalence rate of cervical premalignant changes vary according to which con- Fertility and Sterility

11 traceptive method is initially accepted by women entering a family-planning program? The IUD and OC acceptors showed similar characteristics: all were black, aged 15 to 44 years, and had lower middle-class incomes. Marital status, age at first pregnancy, and number of pregnancies were similar. For 5164 women with two or more Papanicolaou (Pap) smears choosing the IUD, the crude dysplasia rate was 1.3/100 women. Among 9431 similar OC choosers the dysplasia rate was 2.3/100 women. The calculated risk ratio of 1.5 in this series was considered statistically significant. OC acceptors with Pap smears before initial choice of contraceptive method had a l.4-fold higher prevalence rate of cervical dysplasia than IUD acceptors. For the same groups of women with two smears the crude prevalence rate of carcinoma in situ was women for IUD choosers and 0.34/100 women for OC choosers. These differences were not significant. The group of women studied by Ory et al. 78 was dissimilar to the group of women studied by Melamed et al.75 The patients in the series of Melamed et al. were older and of higher parity, and fewer were black. Another crucial difference was that Melamed et al. 75 compared only OC and diaphragm users, whereas Ory et al.78 compared OC and IUD users. Subsequently, Ory79 conducted a case-control study of 584 women with cervical dysplasia and 148 women with cervical carcinoma in situ, comparing OC versus IUD use. These patients were taken from the same population at Grady Hospital. None of the women with dysplasia and carcinoma in situ had prior abnormal smears, and all had at least two normal smears before entry into the study. Lesions developed over a 2-year period of observation. Diagnoses of abnormal smears were confirmed by cervical biopsies. Controls included 8553 black women matched for age, educational status, marital status, age at first birth, and parity. The control patients had no prior abnormal smears and continued to have normal smears for the 2-year period of the study. Analysis showed a "weak" association between OC use and dysplasia. The relative risk of carcinoma in situ for OC users as compared to nonusers rose linearly from 1.3 (1 to 12 months' use) to 4.7 (> 36 months' use). This trend was statistically significant. Stern et al. 80 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 Vol. 47, No.5, May 1987 enrolled in a family-planning clinic in Los Angeles. The combined OC chosen for the study contained 100 j..lg mestranol and 1 mg ethynodiol diacetate. More than 90% of the non-pill users chose an IUD. The patients with dysplasia and their controls were followed with a Pap 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 OCs showed a significantly increased conversion of dysplasia to carcinoma in situ with extended use (more than 6 years). Analysis was conducted with 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. Other case-control studies before 1977 by Worth and Boyes,81 Thomas,82 and Boyce et al.83 indicated no increased risk of cervical neoplasia associated with OC use. The early analysis from the cohort studies was reassuring. In their 1976 report Vessey et al.22 found no cases of cervical dysplasia among 4217 diaphragm users. The incidence of dysplasia among 3162 IUD users and 9653 OC users was similar (0.28 and woman-years, respectively). There were but 12 cases recorded, and no valid statistical analysis was possible with so few cases. The RCGP reported on only "malignant neoplasm of cervix uteri" in Two cases were observed in OC takers, two cases among "extakers," and four cases among the non-oc takers. These numbers were too small for statistical analysis. They have yet to update this report. The Walnut Creek study46 involving 17,942 women observed for 37,373 woman-years initially reported a statistically significant association between carcinoma in situ and duration of OC 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. A later analysis of their data in confirmed the significance of these preliminary findings. In a 1983 update Vessey et al.85 reported on the incidence of biopsy-proved cervical neoplasia among 6838 parous women taking OCs who had been followed for 10 years in the OFPA study. The control group consisted of 3145 parous women who entered the study while using an IUD. Huggins and Zucker oes and neoplasia 743

12 "Cervical neoplasia" in this study includes biopsy-proved dysplasia, carcinoma in situ, and invasive cancer. All 13 cases of invasive cervical cancer occurred in the OC group (P < 0.05). Both carcinoma in situ and dysplasia also had higher overall incidences in the OC group than the IUD groups, although neither difference reached statistical significance. The aggregated ata for all forms of cervical neoplasia showed a significant association with duration of OC use. The risk for OC users rose from 0.8/1000 woman-years to 2.2/1000 woman-years, whereas the risk among IUD users remained relatively constant at approximately womanyears (Fig. 2). This study has been criticized in part for the lack of data on age at first intercourse and number of sexual partners. The authors sampled 100 women in the study and obtained detailed sexual histories. The number of women with age at first sexual intercourse of 17 years or less and those having more than one sexual partner were similar among the OC users and IUD wearers. The strengths of this study are its prospective nature, large size, and very low rate of loss to follow-up among its patients. These patients will remain under surveillance, and additional cases should add power to future analysis. - Pill IUD 2.0 ; 1.8 E 1.6 g I. 4 o... CI.> Co CI.>... '" u c: O o Total duration of contraceptive use I mo I Figure 2 Risk of development of cervical neoplasia among IUD and OC users with respect to total duration of contraceptive use Huggins and Zucker oes and neoplasia Several large studies reported after 1979 have attempted to determine age at first intercourse, age at first birth, number of sexual partners, incidence of sexually transmitted disease, and other factors thought to be important in evaluating the relationship between risk of cervical cancer and OC use. Harris et al. 86 conducted one of the first casecontrol studies on the risks of cervical dysplasia and carcinoma in situ in which there was ascertainment of age at first intercourse and number of sexual partners. Cases were 237 women with abnormal cervical smears matched to 422 controls. Cervical biopsy specimens were taken on each case and were classified as follows: 65 carcinoma in situ, 81 severe dysplasia, 44 mild dysplasia, and 47 normal histology. Significant risk factors were age at first intercourse, multiple sexual partners, and use of OCs. Statistically significant (P < 0.05) linear relationships were seen for length of use of OCs and risk of severe dysplasia and carcinoma in situ. These associations remained significant after adjustment for number of sexual partners. The NCI undertook a large case-control study in five metropolitan areas in the United States. 87 Incident cases of invasive cervical cancer occurring among women aged 20 to 74 years were accrued over the period 1982 to Controls for the study were ascertained through random-digit dialing techniques that matched to cases on age, race, and telephone exchange. A total of 479 cases and 789 controls were identified. Interviews elicited detailed information on contraceptive usage as well as demographics, pregnancy history, menstrual history and hygiene practices, sexual behavior, medical events, smoking, diet, and marital and family history. Analysis found that a number of risk factors were significantly correlated with the probability of exposure to OCs. The most significant confounding variable was interval since last Pap smear. This variable exerted substantial negative confounding, because those with a limited screening history were at extremely low risk for never having used OCs and extremely high risk for invasive cervical cancer (five- to sixfold excess risk for those never having a cervical smear in the 10 years preceding diagnosis). The number of sexual partners, age at first intercourse, and history of a nonspecific genital infection, or sore acted as positive confounders. Fertility and Sterility

13 After adjustment for pertinent confounding variables, the risk associated with ever-use of OCs was 1.49 (95% confidence interval, 1.1 to 2.1). In addition there was a significant linear increase in risk (P = 0.003) with increasing duration of pill use (Table 10). There was some suggestion that long-term high-potency pill use was associated with a higher risk. There was no evidence that pill associations varied according to number of sexual partners, age at first intercourse, or years of smoking. Another large multicenter case-control study of cervical cancer and combined OCs is being carried out under the auspices of the World Health Organization (WHO).88 This study is being carried out by collaborating centers in Australia, Chile, China, Columbia, the German Democratic Republic, Israel, Kenya, Mexico, Nigeria, the Philippines, and Thailand. Cases were 726 women admitted to a hospital with a histologically-proved diagnosis of invasive carcinoma of the cervix. Controls were 5246 women who were admitted for treatment of nonobstetric or nongynecologic conditions. Matching was done on the basis of age and residence. Table 10. Relative Risks a of Invasive Cervical Cancer Associated with Varying Parameters ofoc Usage b Con- Relative Cases trois risk 95% CI' Ever-use No Yes Years of use < Age at first use < Years since first use < Years since last use < > arelative risks are adjusted for age, race, number of sexual partners, age at first intercourse, education, interval since last Pap smear, and history of a nonspecific genital infection or sore. bmodified from Brinton et al. B7 cconfidence interval. Vol. 47, No.5, May 1987 To address some of the deficiencies of prior studies the data collection and analysis considered 23 variables of sexual behavior or access to medical care that might have been confounding variables. Included were data on gynecologic and obstetric history, sexual relationships, age at first intercourse, contraceptive history, and prior Pap smears. The variables most strongly related to risk of cervical cancer or use of OCs were total number of pregnancies, age at first sexual relationship, number of sexual partners, and history of treatment for a vaginal discharge. Vaginal discharge was used as an index of infection by sexually transmitted disease. Among women who had ever used OCs the relationship to invasive cervical cancer showed a relative risk of 1.19 (95% confidence interval, 0.99 to 1.44). When data were analyzed by duration of use the relative risk rose in a linear trend and became significant for those patients who had no history of cervical smears and women analyzed by age and center with more than 60 months' use. The relative risk however, did not reach significance when all six variables were considered (Table 11). When duration of use was categorized in the same manner as that of Vessey et al., 85 a similar trend was evident, and a relative risk of 1.63 (95% confidence interval, 1.03 to 2.59) was observed in women who had used OCs for more than 8 years. The patients in this study were taken from populations quite different from that of the British OFPA study85 or the NCI study87 in the United States. The Oxford prospective study85 analyzed white, married British women. The NCI study88 analyzed hospitalized women at both rural and urban settings in the United States. The WHO study88 examined women from diverse geographic, racial, and socioeconomic backgrounds. Because these women came primarily from developing countries, they were drawn from populations with relatively low levels of cervical screening. This approach tends to decrease the risk of selection bias sometimes seen in populations with high levels of cervical screening. These recent reports, like all other epidemiologic studies, suffer from methodologic problems. However, the consistency of their results adds weight to the concern that long-term OC use is associated with an increased risk of cervical neoplasia. Although these results support a direct relationship between extended pill use and an increased risk of cervical dysplasia Huggins and Zucker OCs and neoplasia 745 )

14 Table 11. Relative Risks of Invasive Cervical Cancer in Users ofdcs in Relation to Duration of Use, Adjusted for Various Confounding Variables Relative risks (95% Months of Age and confidence 88 intervals)" OCuse center Six vari No history abies of smears None a ;;. 60 l.71 a a aadjusted for age, center, number of pregnancies, age at first sexual relationship, number of sexual partners, and his tory of vaginal discharge. and cervical cancer, the mechanisms by which OCs might exert adverse effects on cervical epithelium are unclear. There is some evidence that cervical tissue has hormone receptor sites89 and that administration of OCs can result in histologic alterations.90 There has been some suggestion that OCs may alter progression rates of preinvasive lesions.91 They may also act as promoters for other risk factors, including herpesvirus or papilloma virus infections.92 Further studies are necessary to test the biologic possibility of relationships observed in these studies. BENIGN OVARIAN NEOPLASMS Several studies have reported a lower incidence of functional ovarian cysts in OC users as opposed to nonusers Ory et a1. 2 estimated that the rate of hospitalizations prevented was 35/100,000 pill users. This estimate results in approximately 3000 hospitalizations for treatment of benign ovarian neoplasms prevented in the United States per year.96 OVARIAN CANCER Since 1977 more than nine studies have evaluated the risk of ovarian cancer and OC use. All have shown a protective effect of OCs. However, in several of these studies the results did not reach statistical significance. As with other studies that first describe new epidemiologic phenomena, the number of subjects was small, and certain confounding factors were not included in the study designs. The smaller studies did not adequately investigate or control for infertility, nulliparity, and small family size, all of which are 746 Huggins and Zucker DCs and neoplasia associated with an increased risk of ovarian cancer. The Cancer and Steroid Hormone studyl05 investigated OC use and the risk of ovarian cancer. Cases were 179 women found to have newly diagnosed ovarian cancer. These were matched for age and residence with 1642 women with intact ovaries. The study design captured detailed information on contraceptive practices, and 92 other potentially confounding variables. After controlling for age, which was the strongest confounding variable, none of the others appreciably altered the risk estimates. The age-adjusted relative risk of ovarian cancer among OC users was 0.6 when compared to women who had never used OCs. This protective effect became evident within the first year of use, persisted, and increased through 5 or more years of use (Table 12). This protective effect persists after pill use is stopped, and the magnitude of this effect is virtually unchanged for 10 years after OC use has ceased. The public health implications of this protective effect are significant. It is estimated that in the United States there were 18,000 new cases and 11,400 attributable deaths from ovarian cancer in The authors of this study estimate that more than 1700 cases of ovarian cancer are averted each year by past and current OC use among women in the United States.105 UTERINE MYOMAS Estrogens seem to have an association with myomas. Myomas rarely occur before menarche, Table 12. Risk ofdvarian Cance~ Duration of 95% confidence OCuse Relative risk interval None 1.0 (referent) Ever < 3mo mo yrs yrs ;;. 5 yrs Time since 95% confidence last OC use Relative risk interval Never 1.0 (referent) Ever > 10 yrs amodified from the Centers for Disease Control Cancer and Steroid Hormone study.lo5 Fertility and Sterility

15 tend to regress after menopause and may enlarge rapidly during pregnancy or during exogenous estrogen administration. l06 During the early years of OC usage, it was feared that myomas might grow under the stimulation of estrogen contained in the OCs. The presence of myomas has been considered by some to be a relative contraindication for OC use, l and many physicians are reluctant to use OCs in patients who have a myoma of any type or size. At present, there is little objective evidence in the literature to support this concern. The RCGP cohort study2l found a slightly decreased risk of development of uterine myomas in users as opposed to nonusers. Vessey et a!. 22 in their original report found no significant difference in occurrence rates among OC, diaphragm, or IUD users. None of the patients in either of these studies was taking medication containing > 50 ~g estrogen. Ross et a!. in updated the analysis of risk factors for uterine fibroids with data from the OFPA study. As of July 1985, 538 women in this cohort study had had pathologically confirmed fibroids. Women with pathologically confirmed fibroids before entrance into the study were excluded. Five hundred thirty-five controls were selected and matched for age, date of entrance into the study, and place of residence. The study found a significant decrease in risk of myomas with increasing number of pregnancies (relative risk, 1.00 with first pregnancy, 0.47 with second pregnancy, and 0.24 with fifth pregnancy). The risk decreased significantly with increasing duration of OC use (relative risk, 0.80 at 2 years and 0.54 at 145 months). The risk of development of myomas was decreased by 31% in women who had used OCs for 10 years. Data from this series were obtained from women who were using pills containing 50 ~g EE 2, but with varying amounts of progestogen. There was some suggestion that the higher the dose of progestogen, the more protective the OC. Should these data be confirmed by other studies, the presence of myomas should not be considered a relative contraindication to OC use. GESTATIONAL TROPHOBLASTIC DISEASE The potential for persistent trophoblastic proliferation after the initial evacuation of a hydatidiform mole is well documented. 1OB The successful evaluation and treatment of gestational trophoblastic disease depends on meticulous se- Vol. 47, No.5, May 1987 rial measurement of serum human chorionic gonadotropin (hcg) titers. lll, 112 The failure to note a progressive decline in serum hcg after molar evacuation is generally indicative of trophoblastic malignancy. It may take as long as 100 days for the disappearance of an elevated serum hcg level after the termination of the molar gestation. 113 Pregnancy should be avoided for at least 6 months after negative hcg levels are obtained. 1l4 A gestation during this follow-up will produce hcg and confound attempts to detect proliferative disease. It is therefore imperative that contraception be used throughout this interval. The role of OCs as an important method to prevent pregnancy following molar evacuation has been recently reevaluated. Stone et al. 1l5 investigated the effects of OCs on proliferative trophoblastic sequelae in 611 patients after hydatidiform mole evacuation. After molar evacuation, in 16 of 65 patients (24.6%) who had begun using OCs before normal hcg levels were obtained trophoblastic disease developed requiring cytotoxic chemotherapy. In comparison, among those not using OCs during postmolar follow-up, only 43 of 464 (9.3%) required chemotherapy. This study implied that the administration of OCs to patients before the decline in postmolar hcg levels to normal resulted in a twofold risk of trophoblastic disease requiring chemotherapy. In addition OCs were also found to inhibit the decline in hcg levels even in those not needing chemotherapy. Berkowitz et al. 116 analyzed two groups of patients after molar pregnancy to determine the effects of OCs commenced immediately after molar evacuation on the incidence of trophoblastic disease. Patients were comparable in age, gravidity, tumor histology, pretreatment hcg titers, and exposure to prophylactic chemotherapy. Eleven of 58 (18.9%) using OCs and 6 of 42 (14.3%) using barrier methods developed postmolar trophoblastic disease. These differences were not significantly different, and the authors concluded that OCs do not increase the risk of postmolar trophoblastic disease. They recommended their use during the entire interval of gonadotropin monitoring. They further reported no significant difference in the mean hcg regression time regardless of whether a hormonal or nonhormonal contraceptive was used. The conflicting conclusions of these two studies prompted further investigation. Yuen and Burch 117 prospectively studied 194 patients with pathologically confirmed molar pregnancies. One Huggins and Zucker oes and neoplasia 747

16 hundred seventy-seven patients had l3-hcg titers that spontaneously returned to normal. There were no significant differences in the l3-hcgpositive interval among those women who used barrier methods, IUDs, or combined OCs. Ninetythree of 97 OC users took compounds with 50 f-lg or less estrogen. In 17 ofthe 194 patients invasive complications developed and required therapy. Although the numbers are small there was a significantly greater proportion of women with persistent disease who had used OCs that contained > 50 f-lg estrogen. However, in determining high versus low estrogen dosage the authors assumed that EE2 and mestranol were of equivalent potency. There were 21 patients taking OCs containing 50 f-lg EE2. Some authors believe that EE2 may be more potent than mestranol. 118 Had those patients using 50 f-lg EE2 been included in the high-estrogen-dose group the results may have been modified to show no added risk for high-estrogen-dose pills. Morrow et al. 119 studied 149 cases of molar pregnancy from 1977 through Eighty-four patients seen from 1977 through 1980 received estrogen-progestogen OCs after evacuation. Fifty-five patients seen after 1980 used nonhormonal contraceptives. The groups were similar with respect to age, parity, maternal blood type, and race. Gestational age was significantly shorter and the frequency of cases with a preevacuation l3-hcg titer of > 250,000 miu/ml was significantly higher in the nonhormonal contraception group. There was no significant difference in time of regression for the l3-hcg titers between the two groups. On the basis of the few available studies, use of combination OCs that contain 50 f-lg or less ofee2 after evacuation of a hydatidiform mole appears to be safe and effective. Further studies are necessary to elucidate the relationship between high estrogen dose and persistent trophoblastic disease. OCs AND PITUITARY TUMORS Recognition of the complex relationship between serum estrogen concentration and potential augmentation of serum prolactin (PRL) release through effects on hypothalamic-pituitary sensors has led to scrutiny of the role that combination OCs might have in altering these neuroendocrine interactions. Estrogen-specific receptors on the lactrotrope with modulation of mes- 748 Huggins and Zucker Des and neoplasia senger ribonucleic acid by estradiol in PRLsecreting cells have been studied in vitro.120 During pregnancy, estrogen is believed to directly stimulate lactotrope PRL production and release. Progressively rising serum PRL levels throughout pregnancy appear to result from lactotrope stimulation by the concomitant gradual elevation of serum estrogen concentrations.121, 122 Additionally, PRL-secreting pituitary tumors have estrogen receptors, and pregnancy may result in growth of these lesions.123 It has been speculated that OC-mediated stimulation of pituitary lactotropes by estrogen may cause excessive PRL secretion. 8 Continued uncontrolled estrogenic influence might then lead to hypertrophy and hyperplasia of the lactotrope with possible formation of a pituitary PRL-secreting adenoma.124 An awareness of these relationships coupled with a reported rise in the incidence of pituitary adenomas among women of childbearing age has resulted in study of the relationship between the use of combination OCs and pituitary adenomas among various age- and sex-adjusted populations in Olmsted County, Minnesota, during 1935 to A dramatic increase in the mean annual incidence of these lesions was found in women aged 15 through 44 when data after 1969 were compared with that of prior years. This observation led the authors to conduct a case-control study to determine if OCs were associated with this increased incidence of pituitary adenomas. A decreased relative risk (0.5) was found for pituitary tumors in OC users.126 The authors concluded that the apparent rise in the incidence of pituitary tumors among women was due to improved diagnostic capabilities, including advances in radiologic technique and endocrinologic assays. This study involved only nine cases. Coulam 126 noted that although several studies had reported a high prevalence of prior OC use by patients with pituitary adenomas (70% to 84%), the frequency of OC use in the general population was frequently unknown. Sherman et al. 127 carried out a study on the pathogenesis of PRL-secreting pituitary adenomas. Forty-two women with amenorrhea/prolactinemia had histologically verified pituitary adenomas. The authors hypothesized that the estrogen content of OCs presented a greater estrogenic stimulus than the normal menstrual cycle or pregnancy. This relative hyperestrogenic state might stimulate the growth of occult pituitary tumors. Seventy-four percent became symptom at- Fertility and Sterility

17 ic in the immediate postpartum period, during OC use, or shortly after discontinuation of OCs. Sherman believed that these data suggested that estrogens may facilitate expression of a preexisting lesion. Teperman et al. 128 conducted a casecontrol study with 20 hyperprolactinemic patients with pituitary adenomas as cases. Controls were 20 patients hospitalized for appendectomy. The incidence of OC use in the 20 cases was 65% (12 patients) and 20% (4 patients among the controls (relative risk, 4.0; P < 0.025). This suggested association between the use of OCs and pituitary adenomas was noted by other small studies before Because of the paucity of data on this important issue, the pituitary adenoma study group was established. They undertook a large multicenter case-control investigation to further analyze the relationship between OCs and PRL-secreting pituitary adenomas.133 Three case groups consisting of 212 women with adenomas, 119 hyperprolactinemic patients with amenorrhea and/or amenorrhea with normal or equivocal tomograms, and 205 normoprolactinemic women with amenorrhea and/or galactorrhea were matched to neighborhood control subjects. No association was found between OC use and the development of pituitary adenomas within any of the three study groups. The relative risks were 1.33, 1.35, and 0.67, respectively. Further study was recommended to establish whether OCs may promote the growth of a preexisting lesion. Maheux et al.134 conducted a case-control study in which 70 patients with histologically proved prolactinomas were matched with three separate control groups: normoprolactinemic women with secondary amenorrhea, infertile women with normal ovulatory cycles, and hospitalized patients without medical or gynecologic problems.19 The difference in the proportion of OC usage among the four study groups was not statistically significant. The relative risks were 1.1, 1.18, and 1.15, respectively. Shy et al. 135 conducted a case-control study of 72 women with pituitary prolactinemia matched to 303 neighborhood controls selected by randomdigit dialing. A major confounding variable was menstrual pattern. When those patients who were using OCs only for contraception were compared to never-users there was no increased risk of pituitary adenoma (relative risk, 1.3). When patients who were using OCs for menstrual irregularity were compared to never-users, there was a significant increased risk of pituitary adenoma (relative risk, 7.7; confidence interval, 3.7 to 17.0). The data suggest that those patients taking OCs to correct a menstrual disturbance may have had a preexisting, undiagnosed prolactinoma. On the basis of current available data there appears to be no increased risk of development of a pituitary adenoma in normal patients taking OCs. The question of whether women with menstrual irregularity taking OCs represent a highrisk group for these lesions remains unresolved. OCs AND ENDOMETRIAL NEOPLASIA EFFECTS OF ESTROGEN AND PROGESTERONE ON THE ENDOMETRIUM The endometrium is a hormonally responsive tissue layer whose histologic appearance is directly dependent on intrinsic steroid receptor mediated activity.136 The interaction of estrogen and progesterone (P) with their individual cytoplasmic protein receptors results in significant endometrial growth effects. Estrogenic influence results in cellular proliferation and further increase in the content of estrogen and P receptors.137, 138 As estrogen exerts its biologic effects by means of receptors, an increase in the latter facilitates the establishment of an estrogenic responsive mileu. P administration operates in reverse by decreasing levels of estrogen receptors, which results in diminished uterine estrogen response.138, 139 Estrogen and P receptors with the same physicochemical characteristics as those found in normal endometrium have been found in endometrial hyperplasia and carcinoma.140 Some endometrial hyperplasias have been found to have an elevated estrogen and Preceptor content.140, 141 Furthermore, 60% to 90% of hyperplastic tissues contain high Preceptor levels.140, 141 Unopposed estrogenic stimulation is believed responsible for these increased endometrial receptor levels and for the production of hyperplasia.136 Conversely, P administration in patients with endometrial hyperplasia has been found to decrease hormonal receptor content, with the more pronounced effect on Preceptors. 142 There is convincing evidence that unopposed estrogenic exposure leads to a spectrum of endometrial hyperplastic alterations that can progress to carcinoma.143 The risk for carcinoma has been found to correlate well with the severity of the endometrial change. Failure to modify these le- Vol. 47, No.5, May 1987 Huggins and Zucker oes and neoplasia 749

18 sions can result in endometrial carcinoma in a significant proportion of patients.143, 144 The exposure of the normal estrogen-primed endometrium to P converts the tissue to the typical secretory type seen during luteal phase of the menstrual cycle. This cyclic effect of P prevents the progression of normal proliferative endometrium to hyperplasia.144, 145 P has also been used therapeutically to convert a spectrum of hyperplastic lesions to normal histology.144, 145 It is apparent that the delicate balance between circulating estrogen and P levels and their interaction with endometrial cell receptor systems can have profound effects on endometrial growth. ESTROGEN THERAPY DURING THE MENOPAUSE Several clinical studies have shown that unopposed estrogen administration increases the' risk of endometrial carcinoma in postmenopausal patients Consistent and significantly increased relative risks have been observed (Table 13). Ziel and Finkle149 in a case-control study reported that conjugated estrogens appear to have an etiologic role in endometrial carcinoma. The risk-ratio estimate increased proportionately with time, reaching 13.9 for 7 or more years' use. The corresponding point estimate of risk ratio was 7.6. McDonald et al.150 also found that the estimated relative risk of endometrial carcinoma was increased with exposure to conjugated estrogen. The magnitude of the risk was dependent on estrogen dosage as well as duration of use, with the relative risk being increased to 7.9 at 3 years' use and beyond. Certain objections and criticisms have been raised with respect to these studies: (1) diagnostic surveillance for women taking estrogens may have been increased, so that early lesions would be diagnosed more quickly than lesions in patients not taking estrogens; (2) endometrial hyperplasia may have been misclassified as early endometrial carcinoma, and more advanced stages of endometrial neoplasia have not been Table 13. Association of Estrogen Use and Adenocarcinoma of the Endometrium: Case-Control Studies Author Year Relative risk Smith et al Ziel and Finkle Mack et al McDonald et al Antunes et al. 1a studied in adequate numbers; (3) early cases of endometrial carcinoma have inadvertently been treated with estrogens; (4) the history of drug exposure may have been inadequate; and (5) details of estrogen use may not have been sufficient. In 1978 Antunes et al. 151 conducted a large case-control study of the relationship between estrogen use and endometrial cancer. The study was designed to address the aforementioned criticisms of previous work. Four hundred fifty-one patients with endometrial carcinoma were identified (7% stage 0, 70% stage I, and 23% stages II, III, and IV). These patients were matched with 450 controls. Pathologic slides were independently reviewed. Information about drug use by type and duration was obtained. There was no difference in time to physician consultation for postmenopausal bleeding between estrogen users and nonusers. No patient in this study with endometrial carcinoma had inadvertently been treated with estrogens. The overall risk of endometrial carcinoma was sixfold for estrogen users as compared with nonusers. Long-term use of more than 5 years carried with it a 15-fold risk. Despite the failure of casecontrol, epidemiologic studies to prove a causal relationship, the current evidence seems to suggest that postmenopausal use of estrogens in women with an intact uterus is associated with an increased risk of endometrial carcinoma. The addition of a progestogen to estrogen replacement regimens has proved helpful in the prevention of most endometrial cancers.146, 152, 153 Gambre1l146 observed the incidence of endometrial cancer among several groups of postmenopausal women treated with different hormonal replacement schemes from 1975 to 1981: (1) no hormonal replacement, (2) estrogen-only replacement, and (3) estrogen-progestogen replacement. Twenty-eight endometrial cancers were discovered among 5563 women during 20,560 patient-years of observation (Table 14). Patients using unopposed estrogen had the highest incidence of endometrial adenocarcinoma with a rate of 410/100,000 women per year. Nine women not taking hormones were diagnosed with endometrial carcinoma resulting in a calculated incidence of this disease of 258/100,000 women per year. Estrogen-P users were found to have an annual incidence of 68/100,000 women per year, which was significantly lower than both the unopposed estrogen users as well as the untreated 750 Huggins and Zucker DCs and neoplasia Fertility and Sterility

19 Table '14. Incidence of Endometrial Cancer at Wilford Hall USAF Medical Center: r Patient No. of Therapy group years of patients with Incidence observation cancer (per 100,000) Estrogen progestogen 11, users Estrogen users Estrogen vaginal cream users Progestogen or androgen users Untreated women Total 20, amodified from Gambrell. 146 women. Users of estrogen vaginal cream had a significantly lower rate of endometrial malignancy than did oral estrogen users, but the differences with the other subsets was not of statistical significance. Although these data suggest that progestogen administration in this clinical setting is effective in preventing endometrial cancer, it is unclear whether the subsets were comparable in regard to the various known risk factors for endometrial carcinoma (e.g., obesity, hypertension, early menarche, late menopause, diabetes, and nulliparity). SEQUENTIAL OCs Sequential OCs were first marketed in the United States in Their use was prompted in part by an effort to simulate more closely the natural sequence of estrogen-only followed by estrogen-p found during the normal menstrual cycle. The scheme of administration involved estrogen (80 to 100 j..lg) along for 14 to 16 days followed by an estrogen-p combination for 5 or 6 days. The progestogen content varied from 2 to 25 j..lg (1). Silverberg and Makowski154 and Lyon155 in 1975 first reported the occurrence of endometrial carcinoma in young women taking sequential OCs. These reports were quickly followed by others.156, 157 A "registry" for endometrial carcinoma in young women taking OC agents was established in Denver in By June 1976 the registry had recorded 30 cases of verified invasive carcinoma of the endometrium occurring in women < 40 years of age who had a documented history of OC use. Twenty patients had documented use of sequential-type preparations; 9 had taken combined formulations, and the type of pill used by 1 patient was unknown. Nineteen of the 20 patients using sequentials had been taking one preparation containing 100 j..lg of EE2 as the estrogen and 25 j..lg of dimethisterone as the progestogen.15s Because of the lack of a population-based registry, the previously mentioned authors were unable to establish whether endometrial carcinoma was more common in women using sequential agents than in the general population, or whether the incidence was merely decreased in users of combined agents. Further epidemiologic analysis of this problem in the United States by casecontrol or cohort studies was not possible. In 1976, the sequential OCs were voluntarily removed from the market by the manufacturers.159 COMBINATION OCs Curently used combination OCs differ from their "sequential" predecessors in administration, composition, and dosage. The addition of a progestogen of higher potency to every pill taken per cycle sufficiently opposes the stimulatory effect of estrogen and prevents hyperplastic growth patterns. Several recent case-control studies found that users of combination OCs have approximately half the risk of development of endometrial carcinoma as compared with women who had never used these preparations This protective effect is evident after 1 year of continuous use. 163 It is unclear whether this protection increases after prolonged use. Kaufman et al. 161 found the magnitude of protection to be directly proportional to the duration of use of combination OCs with apeak of protection at 3 years and beyond. Similarly, Hulka et al.162 found that the risk of endometrial carcinoma was reduced further with 5 or more years of combination OC use. However, Weiss and Sayvetz160 found no relation between duration of use and increased protective effect. The Center for Disease Control analyzed data from its Cancer and Steroid Hormone study to assess the relationship between use of combination OCs and the risk of endometrial cancer.163 The study consisted of 187 patients with endometrial cancer obtained through eight populationbased cancer registries and 1320 controls randomly selected from the same eight locations. Ever-users of combination OCs had a relative risk of 0.5 of development of endometrial cancer compared with never-users (Table 15). Twelve months of combination OC use was necessary to Vol. 47, No.5, May 1987 Huggins and Zucker OCs and neoplasia 751

20 Table 15. Risk of Endometrial Cancer" Duration of OC use Never < 1 yr 1-5 yrs > 5 yrs Time since last OC use Never Ever '" 10 yrs Relative risk Relative risk amodified from Oral Contraceptive Use and the Risk of Endometrial Cancer.163 obtain this beneficial effect. The protective effect did not increase after 5 years' continued use. It did persist for 10 or more years after discontinuation of OCs. They estimated that approximately 2000 cases of endometrial cancer are averted each year by past and current use ofocs in the United States. The protective effect of OCs against endometrial cancer has significant public health implications. There remains some disagreement regarding the duration and magnitude of the protective effect after discontinuation of OCs. Several studies have observed a persistent effect for 5 to 10 years, whereas others have noted a loss of this protective effect within 3 years.160, 162 oes AND LIVER TUMORS In 1972 Horvath et al.164 first suggested a possible association between OCs and ultrastructural findings in the well-differentiated hepatoma. The following year Baum et al. 165 described seven women, all OC users, in whom benign hepatic tumors developed. These lesions were reported as benign hepatic adenomas. Subsequently, a number of reports indicating an association between OC usage and occurrence of liver tumors have appeared The histopathologic diagnosis has been variously reported as focal nodular hyperplasia, adenoma, hamartoma, benign hepatoma, solitary hyperplastic nodule, and focal cirrhosis. Reports of these tumors occurring in young women taking OCs immediately engendered grave concern, because before 1970 benign liver tumors in young women were encountered only rarely. Keifer and Scott168 reviewed the literature and were able to find fewer than 80 cases before The Hepatic Branch, Armed Forces Institute of Pathology, and the Family Planning Evaluation Division, Bureau of Epidemiology, Center for Disease Control, in 1977 showed an increasing risk with increased duration of usage170 (Table 16). Each of 79 living women who had a hepatic adenoma was matched with three neighborhood controls in a case-control study. These groups were similar with regard to age, race, education, marital status, and religion. In addition to duration of use, the study suggests that women 27 years and older who have used high-hormone pills for 7 years are at greatest risk for development of hepatocellular adenoma. A liver tumor registry was established at the University of California School of Medicine at Irvine in June Nissen et al. 167 reviewed the literature and the data from the 71 cases at the Irvine Registry in This report confirmed earlier experience regarding patterns of usage in that 64.2% ofthese patients had taken mestranolcontaining compounds for 71 % of the time, and only 17% had taken EE2-containing compounds for 9.6% of the time. Approximately 85% of the patients had used an OC for more than 4 continuous years. Nissen et al.167 pointed out that this preponderance of mestranol-containing compounds may have been more apparent than real because the mestranol-containing brands were produced and marketed before the availability of EE2-containing compounds. Nissen et al.167 felt that a statistical analysis was not possible and awaited further analysis oflarger numbers of patients. Spontaneous rupture of the liver occurred in 18 of these patients, resulting in eight deaths. In 1977 Keifer and Scott168 surveyed the available literature and reported 138 cases in United States literature and added their own cases. This report confirmed the predominant usage of mestranol-containing compounds. In discussing the histopathologic diagnosis of these lesions, Keifer and Scott168 thought that the specific histologic type of tumor might have associated significance. Table 16. Increased Risk of Hepatocellular Adenoma in Women with Use ofocsa Duration of use yr Risk ratio amodified from Armed Forces Institute of Pathology, Hepatic Branch and Center for Disease Control, Bureau of Epidemiology, Family Planning Evaluation Division Huggins and Zucker OCs and neoplasia Fertility and Sterility

21 They observed that rupture of the liver did not occur in women in whom the pathologic diagnosis was focal nodular hyperplasia. They also noted that most of the patients with ruptured liver had adenomas. Patients taking OCs and having adenomas were at increased risk for rupture as opposed to nonusers: 30 of 69 users as compared with only 6 of 27 nonusers. Nine women with a history of OC use had carcinoma of the liver. There were 11 deaths from hemorrhage. Of these women who died, three had malignancies and eight had benign lesions. In an attempt to determine more carefully the extent of the problem, the National Cancer Advisory Board requested the American College of Surgeons' Commission on Cancer to conduct a national survey of the extent of primary benign and malignant liver tumors. Four hundred seventy-seven hospitals in the United States searched their tumor registries and reported on all primary benign and malignant liver tumors in male and female patients aged 15 to 45 years from 1970 to A total of 543 cases was uncovered, 378 in female and 165 in male patients. These cases were analyzed as to histologic type, age distribution, and contraceptive usage. Analysis of malignant tumors revealed that the frequency increased with age. This finding mirrors the reported distribution in the general population. However, the frequency of the benign lesions showed a large peak in the 26- to 30-year age group. This peak corresponds to increased use of OCs in this age group. This large increase for benign lesions in the 26- to 30-year age group is true only for OC users and only for benign lesions. Vana et al. 171 confirmed the previous reports of the excess occurrence in patients using mestranol-containing compounds (three to one versus those using EE2-containing compounds). However, Van a et ai,171 found no dose-response relationship and no association with duration of usage. Forty percent of tumors were diagnosed in women exposed for 5 years or less. Hemorrhage was most frequently associated with adenomas and almost exclusively confined to the OC users. ESTIMATED INCIDENCE OF LIVER TUMORS Vana et al. l71 estimated the incidence of benign tumors at 4.9/1,000,000. This figure agrees with the estimate of 11500,000 to 111,000,000 by Baum et al. 165 Garcia et al. 172 suggested an incidence at 0.04/1,000,000 women. Vol. 47, No.5, May 1987 These low estimates of occurrence rates were confirmed by Vessey et al. 173 They searched the records of patients enrolled in the RCGP Oral Contraception study (116,000 woman-years' exposure in pill takers) and the OFPA follow-up study of women using different methods of contraception (more than 83,000 woman-years' exposure), and no case of benign or malignant liver tumor was found. In addition, the records of the Oxford Linkage study were searched. This study covers the hospital admissions and deaths in a population of more than 1,000,000. No benign liver tumors were found in women of childbearing age from 1970 through One case of benign liver tumor was found in a 23-year-old woman taking OCs for 2 years in a search of the Scottish National Diagnostic Index for the years 1968 through The system covers hospital admissions and deaths for a population of approximately 5,000,000 people. CLINICAL ASPECTS Although benign, these tumors may be life threatening because of their tendency to spontaneous hemorrhage with resultant death. The patient at highest risk for spontaneous hemorrhage seems to be an OC user who has a large mass of the hepatic cell adenoma histologic type and who has taken a high-dose combined pill for more than 4 years. The lesion can first present itself as an asymptomatic mass, but the majority of patients initially complain of epigastric or right upperquadrant abdominal pain. Unfortunately, a significant number of these patients also present with signs of intraperitoneal hemorrhage and shock. Timing may be significant in that some of these lesions seem most prone to rupture at or about the time of menstruation. 165, The standard blood liver function tests are of little value in diagnosing these lesions because no consistent abnormalities are found. Computerized tomography, ultrasonography, and liver scan offer the most accurate diagnostic approaches. The need for confirming tissue diagnosis must be weighed against the risk of hemorrhage caused by needle or open biopsy. These lesions are very vascular, and biopsy alone is attendant with significant risk. A number of the reported deaths have occurred secondary to attempts at resection. There is evidence that these tumors will spontaneously regress after OC use is stopped. 165, Pregnancy, with the resultant high levels of sex Huggins and Zucker oes and neoplasia 753

22 steroids, may have a particularly stimulating effect and increase the propensity for these lesions to hemorrhage. 177 For asymptomatic lesions the best and safest course of management would be to discontinue the OCs, urge the patient to avoid pregnancy, and await spontaneous resolution of the lesion. COMBINATION OCs AND MALIGNANT LIVER TUMORS Investigation of the possible relationship between OCs and liver cancer has provoked considerable controversy. Synthetic sex steroids are believed to potentiate cholestasis, hypervascularity, microsomal enzyme induction, thrombogenesis, and blood vessel wall thickening, thereby facilitating tumor development.178 Additionally, steroids can induce hepatic neoplasia in mice and in patients receiving anabolic steroids for anaplastic anemia or infertility The C-17-substituted anabolic steroids, oxymetholone and methyltestosterone, have been specifically implicated in the induction of hepatocellular carcinoma. These compounds closely resemble the C-17-substituted 19-norsteroids used in OCs. Although a direct oncogenic effect remains unproven, these C-17 alkylated steroids are known to promote proliferation of smooth endoplasmic reticulum and production of microsomal hydroxylating enzymes.186 Helling et al. 187 reported two cases of hepatocellular carcinoma and reviewed the evidence regarding the association of OCs. They noted the following factors that suggested relationship: (1) women in whom hepatocellular cancer develops tend to be of childbearing age, (2) OCs have been implicated in the induction of benign hepatic tumors, and (3) steroids similar to oxymetholone and methyltestosterone are known to produce malignant liver tumors in men. In a 1983 review of the literature Gala and Griffin188 found the average patient age of the 25 cases of hepatocellular carcinoma to be 31 years with a range from 19 to 44. They noted with concern this young age peak and suggest that it may be indicative of a predisposing extrinsic etiologic agent, such as OCs. Henderson et al. 189 subsequently reported 11 additional cases of malignant liver tumors in young women and found a statistically significant association with OC use. These patients were identified by searching the Los Angeles County 754 Huggins and Zucker oes and neoplasia Population Based Cancer Registry for all new cases of liver cancer in U.S.-born women aged 18 to 39 years from 1975 to Two neighborhood controls were selected for each case. Ten of the 11 patients had taken OCs for varying periods of 6 to 168 months. One patient had been given "hormone" shots of undetermined type for menstrual regulation for 9 months before diagnosis. Six of the 11 patients were taking "hormones" at the time of diagnosis. The 11 cases had an average duration of use of 64.7 months versus 27.1 in the control group. This difference was of statistical significance (P < ). The authors interpret their data to suggest strongly that long-term OC use may cause malignant liver tumors. In 1986 Neuberger et al.191 reviewed a series of 26 women younger than 50 years of age diagnosed with hepatocellular carcinoma in a noncirrhotic liver to determine if OCs had an etiologic role. Eighteen of the 26 patients had used OCs for a median of 8 years. The control group consisted of 1300 women whose history of OC usage was known. The investigators found that although short-term pill usage was not associated with an increased risk of tumor development, there was a 4.4-fold increased risk (P < 0.01) for 8 or more years' use. It was concluded that although the overall risk for development of a hepatocellular cancer appeared to be very low, the association should be recognized, particularly in long-term users of OCs. Similarly, Forman et al.192 carried out a case-control study to investigate this issue. They looked specifically at women aged 20 to 44 who had died of liver cancer between 1979 and Age-matched controls consisted of women who had died of other causes, unrelated to OC use during the same time period. General practitioners' notes were the source of information regarding use of OCs by both cases and controls. Information was available for 30 patients with histologically verified liver cancer (19 hepatocellular carcinomas and 11 cholangiocarcinomas) and for 147 controls. Analysis of the data showed that ever-use of OCs was associated with a relative risk of 3.8 for hepatocellular carcinoma. The relative risk rose to 20.1 (95% confidence interval, 2.3 to 175.7) after 8 or more years' use. OC use did not appear to significantly increase the risk of cholangiocarcinomas. The authors recognized various methodologic problems with their study. However, they suggest that although liver cancer in young women is an extremely rare disease in most areas of the world, their findings imply that Fertility and Sterility

23 a substantial proportion of the few cases occurring within noncirrhotic livers is related to OC use. The validity of these conclusions has been challenged by some who have underlined problems with interpretation of the data, the limited numbers of patients, study design, and data collection between 1978 and Limited data available at present suggest an association between OC use and hepatocellular cancer. The incidence of these tumors is extremely rare. Although there have been anecdotal reports of benign adenomas progressing to malignancy, a cause-effect relationship has not been established. Further studies are necessary to clarify the risk that OC use may pose for the development of hepatocellular malignancy. SUMMARY Combined OCs have been used by millions of women in the United States for more than 25 years. During this time, the steroid content of these pills has been markedly reduced from the high initial levels. All of the new formulations introduced in the past 15 years contain 50 j.1g or less ofee 2 The progestogen components are 1 mg or less of norethindrone, 1 mg ethynodiol diacetate, and mg or less of levonorgestrel. Investigations in the past 6 years have contributed significant new knowledge to our understanding of the relationships between OCs and neoplasia. The pool of ever-users of OCs continues to grow substantially. The lag-time from first use is now well into and beyond the range accepted as necessary to promote carcinogenesis. The numbers of long-term users of OCs continue to grow. The investigative studies are much better able to define critical and confounding data items. The analyses of these data have become much more sophisticated and refined. 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 OCs and endometrial carcinoma have contributed to withdrawal of the sequential formulations from the United States market. The problems in investigating neoplasia and OCs 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 being 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 OCs. BREAST DISEASE The high-dose (> 1 mg) progestogen combined OCs have been shown to have a protective effect on the development of benign breast disease. This protective effect does not appear until 2 years' use and is directly related to the dose of progestogen. The new < 1 mg progestogen pills have not been shown to convey this protective effect. There may be at least two types of benign breast disease, one of which is premalignant and the other not. The OCs appear to protect only against those benign lesions that are not premalignant. Current epidemiologic data show no consistent association (either adverse or beneficial) between OC use and the development of carcinoma of the breast in women. Concerns regarding certain subpopulations (i.e., < age 25 and nulliparous women) persist. Further studies are needed on these specific groups of women. LIVER TUMORS Long-term combined OC 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 than focal nodular hyperplasia. Standard blood liver function tests are of little value for screening diagnostic purposes. Physical examination, ultrasound, computerized tomography, and liver scan are the most useful tech- Vol. 47, No.5, May 1987 Huggins and Zucker oes and neoplasia 755

24 r niques for diagnosis. Biopsy and resection are attendant with significant risk of hemorrhage. There is some evidence that these lesions will spontaneously regress after discontinuation of the OC. Pregnancy and resumption of use may exacerbate these lesions. Current data regarding the relationship between OC use and hepatocellular carcinoma are sparse. Several recent reports have shown an increased risk for this very rare tumor and longterm OC use. Additional studies are needed before any valid conclusion can be drawn regarding this relationship. ENDOMETRIAL HYPERPLASIA Long-term postmenopausal use of unopposed estrogen significantly increases the risk of development of endometrial hyperplasia and adenocarcinoma of the endometrium. Sequential OCs (14 to 16 days of high-dose, unopposed estrogen followed by estrogen-progestogen for 5 to 6 days) were withdrawn from use in the United States in This action was in response to a few case reports of endometrial hyperplasia and adenocarcinoma occurring in young women taking these formulations. Recent studies report a significant protective effect on the development of adenocarcinoma of the endometrium by the use of combined OCs. This protective effect becomes evident after 1 year of OC use, and its magnitude reaches 50%. Approximately 2000 cases of endometrial carcinoma are prevented each year among United States women by long-term OC use. This protective effect seems to persist for some years after pill use has been stopped. LEIOMYOMAS Estrogens appear to be related to the growth of preexisting uterine leiomyomas. Data on effects of low-dose OCs are sparse. The available studies suggest that there appears to be no increased risk of stimulating the growth of leiomyomas. The most recent study suggests a protective effect. If these data are confirmed, leiomyomata should not be considered a contraindication to use of lowdose OCs. demiologic studies that have been able to accurately determine the incidence of this specific disease entity in either case or control populations. Several large studies conducted since 1979 have captured information on the other major risk factors (age at first intercourse and number of sexual partners). The results of most recent studies appear to be in substantial agreement. They report an increased risk of cervical neoplasia that is directly proportional to the length of OC use. These studies, like all other epidemiologic studies, suffer from some methodologic problems. However, the consistency of their results adds weight to the concern that long-term OC use is associated with an increased risk of cervical neoplasia. Although these results are supportive of a direct relationship between extended pill use and an increased risk of cervical cancer, the mechanisms by which OCs might exert adverse effects on cervical epithelium are unclear. Further studies are necessary to test the biologic plausibility of the relationships observed in these studies. GESTATIONAL TROPHOBLASTIC DISEASE The low-dose «50,..,g) estrogen combined OCs are appropriate for contraception in the immediate post-molar evacuation period. They do not prolong the time required for the hcg titers to return to normal nor do they increase the rate of conversion to malignant trophoblastic disease. OVARY OC use prevents the development of functional ovarian cysts. Approximately 3000 hospitalizations for treatment of benign ovarian neoplasms are prevented in the United States each year. There is a similar protective effect ofocs on the development of malignant ovarian neoplasms. More than 1700 cases of ovarian cancer are averted each year by past and current OC use among women in the United States. CERVIX The most important risk factor for cervical neoplasia appears to be infection with the human papilloma virus. To date there are no large epi- Acknowledgments. We wish to extend our gratitude to Pat Stasuk, Angela Mikles, Victoria Wisniewski, and Janice Scott for their preparation of the manuscript. 756 Huggins and Zucker oes and neoplasia Fertility and Sterility

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