Adolescent Coitus and Cervical Cancer: Associations of Related Events with Increased Risk

I. D. Rotkin Cancer Res 1967;27:603-617.

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Cancer Research
VOLUME27
[CANCER RESEARCH 27, 603-617,April 1967]

APRIL 1967

NUMBER4

Adolescent Coitus and Cervical Cancer: Associations with Increased Risk1

I. D. ROTKIN

of Related Events

Cancer Research Project, Kaiser Foundation Research Institute, Kaiser Foundation Hospital, Oakland, California 94610

SUMMARY Five subsamples of cervical cancer patients and matched con trols, totaling 416 subjects in each group, were compared with respect to selected sexual variables. All samples were drawn from the same hospital population as part of a larger multidimensional procedure. Age at first coitus was the variable of greatest discriminatory power, strongly overshadowing all other significant differences, and is postulated as the pivotal variable. Twice as many patients as controls began coitus at ages 15-17, comparatively few began after age 21, and almost none as late as age 27. Patients also differed strongly from controls with respect to age at first marriage, number of husbands, and total number of coital mates. About f of patients compared to J of controls were married by age 21. Twice as many patients had multiple mar riages, and many more patients than controls had multiple sexual mates. Circumcision in mates, a moderately significant variable, was interpreted as a peripheral supporting factor. Sexual frequencies were similar for patients and controls. Parity and gravidity studies resulted only in borderline differences. Results support a host-agent-donor hypothesis, with an unde termined agent (or agents) contributed by the donor male to the host female. Speculation conforms this hypothesis to a multi stage model of oncogenesis. Latency studies show a mean 30-year interval between first coitus prior to age 20 and tumor detection, decreasing linearly thereafter. On the basis of these findings, sug gestions are advanced for clinical detection of those at greatest risk, and for prevention in populations.

significantly earlier time in life than the population from which it was drawn. Most of these patients had experienced first sexual intercourse during adolescence, compared to relatively few con trols for the same span of life. This pattern for first coitus ap peared to change at about age 20 after which distributions showed a heavy excess of controls. The pa]>er concluded with a hostagent-donor speculation for insight into cervical cancer etiology. This pajier will expand the data in support of this relationship, selecting onset of coitus during adolescence as perhaps a pivotal variable from the universe of possible environmental influences under study; also it will extend the host-agent-donor hypothesis. Few new data relating precocious sexual beginnings to cervical cancer have been added recently to the literature. Reviews by Doll (6) and by Lundin et al. (14) have assessed the accrual of information and background regarding environmental variables. Doll (6) and also Christopherson and Parker (4) appear to accept age at first sustained intercourse as directly related to onset of cervical cancer, but this requirement for regularity of coitus calls for evaluation. Since sustained coitus is not characteristic of unmarried women in the United States (11), the issue of initial exposure versus repeated exposures to an influence asso ciated with the coital act may be clarified by some of the data presented later in this paper. MATERIALS AND METHODS

Data were obtained by questionnaire, all uniformly adminis tered by me, and all material was coded and committed to IBM 1401 digital computer. End results were retrieved from IBM 7090/4. Many of the results are taken directly from printouts, with manual collapsing into suitable classes. Statistical Treatment. Where useful, ordinary measures of INTRODUCTION central tendency and dispersion are shown under tables. Addi A previous paper (20) reported preliminary material showing tionally, simple ratios and/or X2tests may be calculated to show that a group of cervical cancer patients had begun coitus at a significance and/or homogeneity. For convenience, accompany ing probability levels (P) are shown as taken from nearest 1This investigation was supported by PHS Grant CA-09684 values in standard tables. Since some / and X2values are extreme, a maximum reading of 1 X IO"6 was used as the greatest prob from the National Cancer Institute, NIH, USPHS. Received August 23, 1966; accepted December 8, 1906. ability level of i values, with (much less than) to indicate APRIL 1967
603

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/. /;. f-otkin
greater strength than < (less than). Similarly, extreme values of cio mas (Table 3). Excluding microinvasives, almost 48% of P for high X2 results are taken as a maximum level of 1 X 10~7 invasive carcinomas were Stage 1. Although the entire fund of since Boyd's nomogram for X2now is available (3). As before, <3C available invasive carcinoma patients was taken for study, the percentage of in situ carcinomas reflects only a sampling of the denotes greater strength than <. Composition of Samples. To preserve clarity, the ternis large in situ carcinoma ix>pulation in these hospitals. Distribu sample and subsample denote studied groups, whether patients tion of these lesions was similar for the different classes of race or controls. The term subsample is used further as identical with and religion. Almost 90% of invasive tumors were squamous cell carcinomas, replicate in the original paper (20). consistent with general incidence and hospital experience. The investigated series total 416 patients and 416 comparison controls, all drawn from the membership of the Kaiser Founda Another 8% were adenocarcinomas, and other tumor types were tion Health Plan, served by the Kaiser Foundation Hospitals relatively rare (Table 4). and the Permanente Medical Groups in the San Francisco Bay Table 5 shows distribution of patients by ages at detection. Modal group was the class of ages 40 to 44, with similarity of Area and Los Angeles metropolitan regions of California. Four subsamples were drawn from hospitals in the San Francisco Bay frequencies for classes ranging from ages 30 to 59. An average of Area, and the fifth from two hospitals in the Los Angeles Metroabout 3 years elapsed between detection and interview. The age ]x>litan Area (Table 1). Controls were taken from each hospital range for detection and interview covered the full adult life where patients were found, matched in pairs by age, race, and span, which also may be taken as the period of biologic maturity or )x>stadolescence. Invasive carcinoma patients were parallel religion. to this distribution, and in situ patients showed a peak of detec tion from ages 35 to 49. The distribution for Caucasian women RESULTS followed the general pattern because it was the larger part of About of 85% of patients and controls were Caucasian; another the total sample, but the Negro group was limited in size and 12% were Negro (Table 2). Seventy-five per cent of the total conformed crudely. samples were Protestant and 22% were Catholic. All other Age at First Coitus. For this regional population between classes by race and religion were very small. The largest single 2% and 3% of women had never exi>erieneed a coital act class, the Caucasian Protestant group, was 63% of the total (Table 6). In comparison, every patient in the cervical cancer samples. group had been exjiosed to heterosexual intercourse, although About 23 % of the total sample of patients had in situ cartotal coital exposure for some of these patients was limited to few acts. This universality of sexual activity may suggest a TABLE 1 requirement for penetration of a contaminating instrument, the iienis, into the milieu within which the cervix exists. Size of Subsamples and Total Samples Mean coital onset was age 18 for cervical cancer imtients com ofsubjects"5499986897416Totals108198196136194832 No.i2345TotalsDescription"Pilot Subsample pared to age 21 for the general hospital population (Table 7, Chart 1). Forty-two % of the patients ex)>erienced a first coital act between ages 15 and 17, compared to half this frequency for SFBA1960, study, SFBA1961, controls. More than 80% of all patients had entered coitus by SFBA1962-63, age 20, compared to about 50% of controls, a large difference but SFBA1963-64, a dilution of the stronger result where more than 50% of pa LAMANo. tients began first coitus by age 17, compared to 28% of controls. Taken as a continuoas distribution (t test) or as a distribution of age classes (X2), the significance of these results is extremely strong and is more intense for the total of 5 subsamples than was SFBA, San Francisco Bay Area; LAMA, Los Angeles Metro predicted by the first 2 subsamples (replicates) in the earlier politan Area. *Since patient and control subsamples are matched, they are report (20). A patient /control comparison ratio shows a moderate equivalent in size. excess for patients under age 15, a twofold excess for patients TABLE 2 Composition of Cervical Cancer Patient Group by Race and Religion (Controls Matched)

RaceCaucasianNegroOrientalAll

otherNo.50207%1.20.00.50.01.7TotalsNo35251741684.612.31.71.4100.0

otherTotalsReligionProtestantNo.2624722313%63.011.30.50.575.2CatholicNo.80434!)1%19.21.00.71.021.9JewishNo.50005%1.20.00.0

r><)4

CANCER RESEARCH VOL. 27

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Adolescent Coitus and Cervical Cancer

TABLE 3 Classification of Tumors by Clinical Staging

In situMicroinvasiveStage 1Stage 2Stage 3Stage 4TotalsNo.972319772223414%23.45.647.617.45.30.7100.0

Classification
typeSquamous

TABLE 4 of Invasive Tumors by Cell Type (N = 317)

Tumor

carcinomaAdenocarcinomaAdenoacanthomaAnaplastic cell

Table 10 presents the 5 individual subsamples. The strength of result for earlier first coitus of patients persisted for each. The age class of strongest effect was from 15 to 17, the central ]ieriod of adolescence. All subsamples are homogeneous by X2, and rela tive congruence of the distributions is shown in Chart 3. For in situ and invasive patients (data not shown) the trend continued; for Caucasian patients and controls the effect was as strong as for the total sample. The general meaningf ulness of this result persisted for Negroes, but with a dilution of effect. Table 11 is an over-and-under test by X2 to emphasize differ ences at cutoff i>oints for ages at first coitus by individual and combined subsamples. Although the strength of the effect varied, the trend was uniform for each. Interaction and Relative Significance of Marriage and Coitus. The position taken here, as in the original study (20), is that coitus may be the larger or pivotal event to which other secondary variables relate. One of these subordinate dimensions is marriage. Age at first marriage has long been rejxjrted in cervical cancer studies as an event of greatest relationship with increased risk of cervical carcinoma. It is still seriously so disTABLE 6 Sexual Partner Preference for Total Samples
(N 416)41110400Controls = (N 416)40411091 =

carcinomaMixed squamous-and-adenocarcinomaAdenomucous carcinomaUndifferentiated carcinomaNo.2792412911%88.07.60.30.62.80.30.3

Distribution

TABLE 5 by Ages at Detection of Cervical Cancer in Patients (N = 415)

onlyHomosexualMixedInfrequent Heterosexual

(years)21-2425-2930-3435-3940-4445-4950-5455-5960-6465-6970-78No.21551627064545126128Mean Age category

homosexualNo experienceUncertainPatients sexual she has experimented

1Although this patient is a homosexual, with 4 different male contacts.

TABLE 7 Comparative Distribution of Patients and Controls by Age at First Coitus (Totals)

404)No.2587106994542%6.221.526.224.511.110.420.85.4Ratio1.42. -= 416)No.3717512849198%8.942.130.811.84.61.918.03.5Controls(N (N (years)<1515-1718-2021-2324-26>26MeansStandard Age

ages (yr.):

Total sampleIn segmentMicroinvasive situ segmentInvasive segment%0.53.612.314.916.915.413.012.36.32.91.945.942.441.647.0

between ages 15 and 17, a dilution of the effect for patients be tween ages 18 and 20, and reversal of the trend after 20, when controls are shown generally to have begun coitus (see Chart 2). Tables 8 and 9 are presented to explore this relationship. When the total sample is tested by race, the Caucasian results conformed to those in Table 7. The smaller Negro patient group also experienced earlier coital onset compared to their controls. Differences for age at first coitus between in situ patients and their controls corresponded in trend to the expected. The result for invasive carcinoma patients was stronger, perhaps as a con sequence of the greater number of cases.
APRIL 1967

deviationsRanges TestsPatients 6-45 t ratio = -9.0, P 1 X IQ-6; X2 (5 df) = 84.4, P 1 X 10-'; later onset first coitus for controls. " Test values were computed excluding 9 additional controls with no coitus, inclusion of which in the >26 class would increase the significance of the differences obtained.
(HI.-)

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/. D. Rotkin 50Xp=18

11

15 AGE

19 AT

23

27 FIRST

31

35

39

43

47

COITUS

CHART 1. Distributions for total patients and controls by age (years) at first coitus. Subscripts p and c are used to distinguish between means of patient and control groups. cussed in the literature despite the difficulty of ascribing associa tion of a contractual agreement between men and women with cervical pathology except in terms of a larger order of influence that is correlated with and includes marriage. Several studies (2, 4, 6, 13, 26, 28) have shown or suggested that coitus bears the stronger relationship to increased risk. My own paper (20) gathered together much of this evidence and proposed that coitus is an event independent of marriage, yet is universal in all mar riages. It is a fundamental biologic process in higher organisms, carries a contaminating instrument directly to the cervix, and can strategically be identified in the several aspects which are effective upon tissue: infection, psychologic change, hormonal reaction, reproduction, and association with all other relation ships which have been described. These include parity, gravidity, abortion, circumcision in mates, and marriage. Table 13 shows that about half of all patients and controls had experienced pre marital intercourse. Table 12 is the distribution showing first marriage by age classes. The difference between patient and control groups sup ports the celebrated finding of many studies that relates early age at first marriage to greater risk of cervical cancer, and the significance of the difference between patients and controls is as strong as expected. However, the result is not as extreme as that shown for age at first coitus in the previous tables, ascribable to a subtraction of effect by premarital beginnings of coitus (see CANCER RESEARCH VOL. 27

50PATIENTS CONTROLS

<15

15-17

18-20

21-23

24-26

>26

AGE CLASS

CHART2. Percentage frequencies for distributed age classes (years) at time of first coitus. Ratios reflect excesses.
GOt

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Adolescent Coitus and Cervical Cancer

TABLE 8 Comparative Distribution of Patients and Controls by Age at First Coitus (by Race)

(years)<1515-1718-2021-2324-26>26MeansStandard Age 352)No.2214511348168%6.241.232.113.64.52.318.33.48-44Controls -344)No.196496874137%5.518.627.925.311.910.821.15.56-45t (N 51)No.6238833%11.845.115.715.75.95.918.14.311-30t -51)No.152311110%29.445.121.62.02.00.015.72.98-24Controls(N(N

deviationsRangesTestsCaucasianPatients(N

ratio X1(5df) = -8.2, P 1 X 10-; lateronset = 73.8, P 1 X Kr7; Caucasiancontrols.NegroPatients first coitus for

ratio =13.8, = -3.4, P < 0.001;Xs (5 df) firstcoitus P < 0.02; later onset for Negro controls.

Comparative Distribution

TABLE 9 of Patients and Controls by Age at First Coitus (by Pathology)

situPatients

(years)<1515-1718-2021-2324-26>26MeansStandard Age

(N-97)No.1039271434%10.340.227.814.43.14.118.13.98-30 (N-93)No.61928181111%6.420.430.119.411.811.820.85.610-45 317)No.2713510035164%8.542.631.511.05.01.317.93.48-44 (N 313)No.196979813431do6.122.025.225.910.99.920.85.46-44 (N =

deviationsRanges TestsIn ratio= 3.9,P < 0.0001;X' (5 df) = t ratio = -8.0, P < 1 X 10-; X' (5 df) = 70.7, P 1 X 10-'; 16.0, P < 0.007 later onset first coitus for in siluControls controls.InvasivePatients later onset firstControls coitus for inva sive controls. and of events associated with onset. A necessary first step is to establish duration of latency. If there is an association of first coitus with initiation of cervi cal cancer, subtracting age at first coitus from age at detection might serve to measure latency. As long as this effect of first coitus persists, the latent period should remain constant. Upon weakening of the effect, a change in latency might be expected. Tables 14 and 15 show a mean latency of approximately 30 years for classes beginning coitus before and during adolescence, with a steady decrease thereafter. Another comparison base for a 30-year latent period is derived from animal work. The life span of the mouse under laboratory conditions may be taken at about 2 years, or for convenience,
607

Table 13). About of the patients were already married whereas almost j of the controls had yet to be married by age 21. For the proportion of women who had not experienced premarital coitus, age at first marriage was age at first coitus. Latency. The interval between application of carcinogen or implant and expression of the tumor in experimental animals is well known. This latent period often is overlooked in studies of human cancers. In consequence, the full imjjort of contributing events cannot be assessed unless sufficient time elapses between studied factors and analysis of populations, which makes pro spective studies difficult, if not impossible. In retrospective studies subtraction of presumed mean latent periods from modal ages of incidence may provide estimates of ages of carcinoma initiation, APRIL 1967

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I.D. Rotkin
Distribution TABLE 10 by Siibsamples of Patients and Matched Controls for Age at First Coitus

coitus00050301000.00.00.05.20.03.10.01.50.00.0 (years)<1SNo.34961245487%5.67.59.16.212.24.17.45.98.27.215-17No.22133020441627135225%40.724.530.320.644.916.339.719.153.625.818-20No.16113 class Subsample1.

Patients (N = 54)Controls 53)2. (N = Patients (N = 99)Controls 97)3. (N = 98)Controls Patients (N = 98)4. (N = Patients 68)Controls (N = 68)5. (N = Patients 97)Controls (N = (N = 97)Age X2 for homogeneity, homogeneous.
-<AGE 20H

patients

and controls, combined (24 df) = 31.1, P < 0.2; total sampling is

50-

15 AGE AT FIRST COITUS. PATIENTS

19

23

27

31

35

39

43

47

AGE AT FIRST COITUS,

CONTROLS

CHARTS. Superimposed curves to show relative congruence of distributions age (years) at first coitus. (iOS

for 5 subsamples of patients

(left) and controls (right) by

CANCER

RESEARCH

VOL. 27

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Adolescent Coitus and Cervical Cancer

cancer in women is between 45 and 50 years of age, deducting 30 years (as parallel to 30 weeks in the mouse) from this age range results in ages 15 to 20. equivalent to that period at which age at first coitus is most significant in this and in all other studies. One could speculate that the carcinogenic contaminant found harbor in cervical tissue at this time. A review of mouse work (27) also shows a latency range of about 10 to 64 weeks, although much of the exi>erimental design (arbitrary sacrifice of animals) is not useful in determining true latent i>eriods. It is interesting to compare this with latency be TABLE 11 tween first coitus and detection in humans, 7 to 61 years (Tables Comparative Frequencies of First Coitus Under and Over Ages 17 and 20 for Patients and Controls (by 14 and 15). Subsamples)" Table 15 is restricted only to patients with invasive carcinoma since the detection of in situ cancers is largely a fortuitous event, underX 17 and underX* 20 and occurring earlier from checkup procedures with the Papanicolaou Xo.i2345CombinedAge Subsample smear test. As in Table 14, covering all patients, the latent ]>eriod df)6.28.626.018.029.778.9p0.010.0035X (1 df)2.33.527.87.216.249.5p<0.14<O.OG2x (1 for invasive patients alone hovers at around 30 years for classes up to age 20, and decreases gradually as expected after age 20. Sexual Frequencies. Although sexual frequency often has 10-'2 i<r7<0.007<6 been proposed as an influence u|>on increased risk of carcinoma, 10-'<1 X Masters (15) has shown that there is minimal opportunity for IO-6i X 10-'1 X traumatic contact between glans and cervix during the coital act. The notion that an earlier beginning of coitus implies greater x io~7Age X 10~7 sexual frequency also is unsupported. Premarital coitus is spo radic for the American woman (11), and since much of first " Class of "no coitus" included in over 17 years, over 20 years. coitus is premarital, the number of coital experiences during adolescence is not great. The woman who maintains an active TABLE 12 sexual schedule after marriage may surpass quickly the early Distribution by Age at First Marriage (Totals) coital beginner in terms of accrued acts, despite her late start. 389)No.799144754114612%1.825.437.019.310.53.61.50.30.519.913-41Controls (X = 378)No.45598976222151312%1.114. (X = Convincing data for sexual frequencies are difficult to amass. Age (years)<1515-1718-2021-2324-2627-2930-3233-35>35MeansRangesTestsPatients Variability for different ages and times in life is great for indi viduals and within )x>pulations. Accuracy is limited by recall and personal involvement. An effective procedure is to correlate fre quency information with a i>eriodin life for which there is equiva fi25.925.616.45.84.03.43.222.513-49 lence for most women in the study, and for which there is reason able vividness of remembrance. The period chosen as a suitable marker was most frequent coitus on a sustained level, but ex cluding honeymoons and reunions. Results are shown in Table 16. Since the statistic is crude, the small mean difference of 1 coital act per month cannot be taken as a serious departure by ]>atients from the general population. For information which de|x>nds largely ujKin memory, and which can be alloyed by many other considerations, a high level of significance would be required for any meaningful interpretation. The distributions are quite close ratio = -7.5, P < 1 X IO"6; X2 (8 df), all with very little difference between patients and controls for all classes = 52.1, P < 1 X 10~7; X2 (1 df), for 21 classes showing any appreciable coital frequency. From this and older = 39.8, F 1 X 10~7. table, and from the physiologic nature of the sexual union be All tests, later marriage for controls. tween human male and female, no influence u]X)ncervical cancer can be attributed to increased sexual frequency. Relative Exposure to the Sexual Environment. An alter TABLE 13 native and more promising approach is determination of differ Marital Status at Time of First Coitus (Totals) ential exposure to varying numbers of male sexual partners, in 411)No.222189%54.046.0Controls (N = 398)No.188210%47.252.8 (X or out of marriage. For both situations patients have experienced StatusPremaritalMaritalPatients appreciably more sexual contacts with more individual men. Table 17 distributes numbers of marriages for patients and con trols, and shows a heavy excess of multiple marriages for pa tients. Twice as many patients as controls were married 2, 3, and 4 times, and the difference is highly significant. This is a X2 (1 df) = 3.7, P < 0.06; more controls married at time of variable that can be applied separately to in situ and invasive patients. From Table 18, the in situ patient parallels the invasive first coitus. APRIL 1967 G09 100 weeks. Under ideal conditions a human female might be expected to live about 100 years. One week of mouse life, then, might be taken as equivalent to about 1 year of human life. From von Haam and Scardili (27), Reagan and Wentz (18), and other investigators, the modal latent period of cancerogenesis induced in the mouse cervix ranges from about 20 to 40 weeks, depending upon the strength of the carcinogen, with an apparent mean of about 30 weeks. Since the peak incidence for cervical

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I.D. Rotkin
TABLE 14 Latency Period Between Age at First Coitus and Age at Time of Detection of Cervical Cancer (Total Patients)
coitus<15(N Duration latency (years)<n11-1516-2021-2526-30 37)No.11557 = at first 414)No.1338596572 (N173)No.412273332 (N = 128)No.512191417 (N 49)No.07511975221%0.014.310.222.418.4 (N = 19)No.1332511210%5.315.815.810.526.3 (N 8)No.23002 =

3.19.214.315.717.4

31-3536-4041-4546-50>50Means 15.68.17.54.61.727.8 2026744%3.99.414.810.913.3 15.620.35.53.13.128.8 14.310.24.14.12.027.4 5.35.310.55.30.025.9 27141383%2.36.915.614.118.5 00100%25.037.50.00.025.0 0.00.012.50.00.019.5 605429168% 14.513.07.03.91.927.7 58410%2.72.713.513.518.9 13.521.610.82.70.030.07-4815-17

RangesAge

8-6118-20

7-5321-23

12-5224-26

10-46>26(N

8-41Total

7-61

TABLE 15 Latency Period Between Age at First Coitus and Age at Time of Detection of Cervical Cancer (Invasive Patients)
coitus<15(Nat first

317)Xo.927364457524726136%2.88.511.413.918.016.414 (N Duration 4)No.0200100100%0.050.00.00.025.00.00.025.00.00.023.711-41Total (N = 134)No.3818202523141382%2.26.013.414.918.617.210.49.76.01.529.38-6118-20 (N = 102)No.4121211121821633%3.911.811.810.811.817.620.65.92.92.931.57-5321-23 (N = 34)No.0328954201%0.08.85.923.526.514.711.85.90.02.928.512-5224-26 (N 16)No.1231511110%6.212.518.86.231.26.26.26.26.20.025.910-46>26 (N = 27)No.1014557310%3.70.03.714.818.518.525.911.13.70.031.97-4815-17 latency (years)<1111-1516-2021-2526-3031-3536-4041-4546-50>50MeansRangesAge

patient by trend. Although the level of significance is not as high for the in situ patient, she is different from the general popula tion in having been married more often. Significance of exposure to multiple men persists when marriage is eliminated as a variable in favor of total numbers of mates during the sexual experience of sampled women. Table 19 shows that many more patients have had coitus with 2 or more different men than have controls. The difference is perceptible in the class of 1 mate only, for which there are almost twice as many con trols. The excess of patients who have been exposed to several or many men is apparent in the distribution and for each individual class of multiple mates. In situ and invasive patients may be separated also for this 610

variable (Table 20). Again, the in situ patient conforms to the trend, although not as strongly as does the invasive patient, in that exixxsure to more sexual mates appears associated with her lesion. The meaningfulness of Tables 17-20 lies in a greater probabil ity of contamination to the female from individual males. Ex posure to more males increases the likelihood that an agentcarrying male might be encountered. Circumcision of Mates. Dejiendency of the female at risk u[x>n the coital mate focuses upon a search for male properties which may contribute to probability of cervical cancer. The most discussed of these is lack of circumcision. Resolution of this variable never has been secure, and there has been a general preCANCER RESEARCH VOL. 27

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Adolescent Coitus and Cervical Cancer

exposure to lack of circumcision by the first mate dwindles to a borderline level, although fewer patients still were ex|x>sed to circumcised men. In a further test of the role of circumcision as 415)No.01871131114261%0.00.221.027.226.710.114.712.00.1-84Controls (N 414)No.94811241025242%2.21.019.630.024.612.610.111.00-99 (N = it affects cervical pathology, circumcision is held constant in Coital acts per monthNone<11-45-910-1415-19>19MeansRangesPatients Table 23, and age at first coitus is tested for variation between patients and controls. Here, differences between patients and controls persist whether patients were exposed only to circum cised males, or to one or more uncircumcised mates. Whether or not the female had contact with a noncircumcised male does not affect the increase in risk associated with earlier onset of coitus. The excess of controls who had coitus only with circumcised men requires explanation. Unless this results from the difference of percentages of mates in the doubtful class, it may be a conse quence either of the favorable harbor found by contaminants under the prepuces of patients' mates where, in the absence of good hygiene, they may be contributed to the cervix; or else an In order to avoid bias, 99 is taken as a convenient end point association of more prevalent circumcision with higher socioto establish a valid range for comparison with patients. This case economic classes. It has been shown repeatedly that cervical represents a prostitute with estimated 400+ acts per month at peak activity. cancer is less prevalent among the better educated and more economically secure population strata, but that there is less TABLE 17 carcinoma in higher socioeconomic classes because there is more Number of Marriages for Total Matched Samples circumcision is debatable. My own position would be that con taminants may be held viable or ready under the prepuce until 416)No.2028290213302114%4.867.821.65.10.772.627.41.3<Mt 416)No.22141474112216200%0.551.435.39.82.952.048.01.60-4Controls (N = (N = ofmarriages0i2340 Number exposed to the cervix. Gravidity and Parity. Another area which may relate to sexuality and cervical cancer is the effect of pregnancy and/or delivery upon the cervix. In Table 24 the distribution rather than an}' doubtful significance should be scrutinized. There is hardly enough difference in mean numbers of pregnancies and deliveries to warrant a conclusion of much greater fertility or activity on the part of patients. Distributions show patients as slightly more gravid and parous, but in no class is there an appre 12and ciable excess that cannot be depended ujxm the more extensive moreMeansRangesTestsPatients and coital experience associated with lower socioeconomic classes (11), or to the earlier establishment of coitus in the lives of patients. The levels of significance are quite minimal compared to the ratio = 6.8, P < 1 X 10-; X2 (4 df), all classes strong results for variables relating directly to adolescence and = 49.6, P IX 10-'; Xz (1 df), for two or exposures to multiple coital mates.
more marriages = 37.8, P < 1 X IO"7. with multiple All tests show excess of patients marriages. TABLE 16 Estimated Greatest Sustained Sexual Frequencies (Totals)

DISCUSSION
With the possible exception of breast cancer, no female-limited tumor has generated as much speculation regarding etiology as has carcinoma of the cervix; and the extent of correlations and refutations is impressive in a medical area where discovery of true association is tantamount to prevention of disease and the saving of life. The growing literature, accelerated in recent years, has evolved into a complexity of separate paradoxes where early marriage per se cannot cause cervical cancer but is always asso ciated with it; where the general ambiguity of "socioeconomic factors" often is hypothesized as fundamental because there are correlated data; and where each of many other discrete influences is regarded as causative. Among these, circumcision of mates has been both demonstrated and refuted, multiple gravidity and parity have been claimed in some studies and denied in others, venereal disease has been declared a direct cause, sustained sexual activity has been presumed as a relationship despite a total lack of evidence, poor hygiene has been suspect as well it may be on 611

occupation with residual aspects, such as what constitutes a true circumcision, rather than a determination of some rationale whereby circumcision may be etiologically implicated. Table 21 shows a difference for circumcision of coital mates between the group of patients and the sample of controls. Many more con trols had experienced coitus only with circumcised men. The significance is considerable and it might be supposed that ex posure to the uncircumcised male is a factor increasing risk of cervical carcinoma, as has long been held. Since the level of sig nificance is not as powerful as results shown for age at first coitus, numbers of husbands, and numbers of coital mates, a closer look is warranted. Table 22 compares exposures of patients and con trols to first coital mates only, where differences might be more perceptible as an effect of the strong relationship of increased cancer risk to adolescence. The significance of differences for
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I. D. Rotkin
TABLE 18 Number of Marriages for Matched Samples, by Pathology
siluPatients Number of marriages012340 97)No.050341125047%0.051.635.011.32.151.648.41.6Controls (N= 321)No.14218711532389%4.467.922.14.70.972.327.71.31-4 (N = 97)No.66520607126%6.267.020.66.20.073.226.81.31-4 (N = 317)No.21631123010165152%0.651.435.39.53.252.048.01.6Controls (N =-

12and moreMeansRanges ajid

TestsIn

1-4 0-3 ratio = 3.6, P < 0.001; X2 (4 df) = 1 5.1, t ratio = 5.7, P < 1 X ir6; Xs (4 df) = 34.9, P = 5 X 10-'; X1 (1 df) for 2 or P < 0.005; X2 (1 df) for 2 or more = 9.7, more =27.8, P = 2 X IO"7. P < 0.002.InvasivePatients All tests show significant excesses of marriages for patients.

TABLE 19 Number of Sexual Partners During Entire Experience of Patients and Matched Controls, Totals
340)No.9166974018127%2.648.828.511.85.30.30.62.02.70 318)No.0951105933948:;0.029.934.618.610.42.81.22.53.7Controls (N = (N =

TABLE 20 Number of Sexual Partners During Entire Experience of Patients and Matched Controls, by Pathology
uPatients(N sii

er0i2,34,56-89-1213-20>20MeansTestsIn Numb 265)No.6134742813127%2.350.627.910.64.90.40.82.62. 238)No.069884917627%0.029.037.020.67.12.50.82.93. = 76)No.33224125000%3.942.131.615.86.60.00.00.02.4X2 79)No.026211016321%0.032.926.612.620.23.82.51.34.0Controls(N -

01 only2,34, 56-89-1213-20>20MeansAccumulative

per 51.5.2 to 1: patients, 29.9; controls, 48.5.X2 or more: patients, 70.1; controls, centages and testsPatients 10-'0 (1 df) = 42.7, P 1 X 80.0.4 to 3: patients, 64.5; controls, 20.0.X2 or more: patients, 35.5; controls, IO"6All (1 df) = 19.9, P = 1 X ofsexual tests show significant mates for patients. excesses

(1 df), 0 and 1 com (1 df), 0 and 1 com pared to 2 and more =29.3, pared more= to 2 and 10-'.X2 P = 1 X 0.09.X2 2.8, P = comparedto (1 df), 0-3 to4 (1 df ) , 0-3 compared 5.9,P 4 and more = 14.2,P and more = 0.0002.All < 0.02.InvasivePatients(N < matesfor tests show significant excesses of sexual patients.

a basis of data and logic; and early onset of coitus has been demonstrated by several workers, including Wynder (28), Terris and Oalmann (26), and in my own paper (20). This seeming confusion has led Lundin et al. (13,14), Terris and Oalmann (26), Wynder (28), Boyd and Doll (2), and others to suggest or to require a center for this circle of related events. There is generalized agreement on one issue: that risk of cervical cancer is altered in the presence of sexual intercourse. Corollaries might be that without actual sexual intercourse there is no risk,

and that coitus is fundamental to many of the significanti}' re lated variables in the literature. Perhaps it would be premature to claim early coitus as the pivotal event around which other variables cluster, but there certainly is reason to believe that such a cluster of factors exists, that early coitus is common to associated components, and that this cluster strongly influences risk. Interruption or disruption of this group of etiologic relaCANCER RESEARCH VOL. 27

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Adolescent Coitus and Cermcal Cancer

TABLE 21 Frequencies by Classification of Circumcision for All Mates of Matched Subjects
onlyNo.71111%17.126.7NoncircumcisedNo.142140%34.133.6MixedNo.134103%32.224.8UnknownNo.6962%16.614.9
miniePatients T t 1

416)Controls (N = (N = 416)Circumcised X2 (1 df) = 10.8, P = 0.001 ; the class of "circumcised only," compared to combined "noncircumcised' and "mixed," showed fewer "circumcised only" for patients. TABLE 22 by Circumcision of First Mate, Totals
415)No.173 (N 405)No.165129 (N =

Distribution

Not circumcised Circumcised DoubtfulPatients

102140%41.724.6

33.7Controls111%40.7

31.8 27.4

X2 (1 df), for circumcised against all others = 5.4, P = 0.02; fewer first mates of patients were circumcised. tionships can be useful in preventing cervical cancer. The deter mination of each component becomes a necessary part of gyneco logic practice in selecting those women who are at increased riskDesignating the pivotal role of early coitus does not neces sarily indicate greatest relationship to increase of risk. Instead, adolescence appears to encompass a period in time when sus ceptibility is at a maximum.2 This age span, largely unexplored, may be the superior and central aspect, and the interaction of environment with susceptible adolescence may be a crucial con sideration. The nature of latency in experimental cancer induc tion demonstrates that initiation of the tumor begins consider ably earlier than its detection, and the powerful evidence from many sources relating increased risk to early onset of coitus also may establish adolescence as the time when prevention can begin. Assessment of Variables. Collecting those influences with an equivalence of statistical strength, 4 emerge which apjiear not only to separate the group of cancer patients from the general hospital imputation under study, but also which seem to be interrelated. These are age at first coitus, age at first marriage, number of husbands, and total number of coital mates. Sexual intercourse is a factor common to all. It is well to remember that virgin and celibate women are known to be without risk, not only because rarely has a woman without sexual experience been reported with a cervical carcinoma, but also because studies designed to test this hyjiothesis with nuns in Catholic orders 2 Total susceptibility contains 2 variable and interacting com ponents, only 1 of which (time of life) is discussed here. The other is genetic, and by this I mean that susceptibility also is a function of genetic diversity. Unless the entire body of genetic literature is invalid, some women are at greatest risk, and others are not at any risk even in the presence of early coitus and other associated events (21), with a risk gradient between these extremes. APRIL 1907

have uniformly supported the conclusion that cervical cancer does not occur without sexual ex]x)sure. Not one of the 416 pa tients studied here had failed to experience a heterosexual contact. The strongest of all associations is age at first coitus. Five subsamples are shown, separately and combined. The congruence of the individual subsample distributions for patients and con trols is convincing with )x>wer that is not often encountered in epidemiologie studies. The age span of greatest effect also is uniform in all subsamples, generally delimiting the period of adolescence. The study of Terris and Oalmann (26) parallels this distribution with data obtained by a different procedure. No study concerned with age at first coitus has failed to show this relationship. As expected, age at first marriage also shows strong impact ii])on risk, but with significance that is considerably less than the effect of age at first coitus. Since about 50' . of sexual onset for these women is premarital, one would e.\|>ect a higher level of relationship for age at first coitus as a primary variable, and less for age at first marriage if coitus is that com|xment of marriage that is responsible for the marital association with cervical cancer. The original reirt (20) proposed a simulation in support of a host-agent-donor relationship, now subject to reassessment by the data in this paper, and perhaps to reexamination for parallels relating to recently developed theories of oncogenesis. If more sexual mates can be taken as an increase of ]wssibly infective contacts, and if it can be said that any given donor male may be a contributor of an initiating agent, then the risk of cervical cancer increases with the chance that a carrier male will be en countered, and this is a function of the total number of coital mates. The Host-Agent-Donor Hypothesis. It seems likely that the s]>eculation ]stulating the female at risk as the host, the male coital partner as the donor, and an intervening vector as his contribution, is a promising wsition in searching for a set of conditions comprising a pathway or model. Several questions arise for discussion, if not resolution, and one of these is the in sistance upon sustained sexuality. It is doubtful that the requirement of "continuing sexual activity" is supported by any study, and although there is a general disinclination to accept a single coital act as causal in any respect, there is no good reason to reject the effectiveness of limited coital activity. If an agent (or diverse agents) exists, and if it (or they) interacts with maximal susceptibility, then such an initiating agent can be contributed by the carrier male to the susceptible female during a given coital act. If malignane}' is a

013

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I. D. Rotkin
TABLE 23 Frequencies of Patients and Controls by Age at First Coitus, Separated into Classes Circumcision of Mates
onlyPatients mates mixedPatients noncircumcised and

Age class(years)<1515-1718-2021-2324-26>26Circumcised 111)No.21336291516%1.811.732.426.113.514.4X2 71)No.32526764%4.235.236.69.98.55.6Controls (X = (X = 276)No.281178136104%10.142.429.413.03.61.4Controls (N = 242)No.205760642219%8.323.624.826.49.17.8X2 (N 69)No.63321630%8.747.830.49.74.30.0Controls (N 51)No.31710687%5.933.319.611.815.713.7 (N =

=0.0005, (5 df) = 22.3, P coitusforearlier first patients.Combined

<0.0001, (5 df) = 45.5, P

coitusfor earlier first

patients.UnknownPatients 9 controls had no coitus.

Data not available for 3 controls. An additional TABLE 24 Distribution of Deliveries and Total Pregnancies for Cervical Cancer Patients and Their Controls

There is some laboratory support for greatest susceptibility during an early period in life, and also for the sufficiency of a single tumor-inducing dose. Huggins et al. (10) achieved peak mammary cancer induction in 50-day-old rats, using 3-methylcholanthrene. In 100- to 365-day-old rats only a small number of carcinomas develoj)ed. In the same study, and in another (9), Number01-23-45-67-8MoreMeansRangesTestsPregnanciesPatients(N.= 415)No.42140125573318%10.133.730.113.78.04.33.30-24Controls 415)No.991801022563%23.943.424.66.01.40.72.00-12X2 415)No.6918810142114%16.645.324.310.12.61.02.30-10Controls(N . 411)No.71133128501613%17.332.431.112.23.93.22.90-27Xa (N single doses or applications of strong carcinogens were found adequate for induction of both carcinomas and sarcomas, all in rats. The Nature of the Agent. From work with animals, from epidemiologie studies, and from conjectures on molecular levels, it is possible to guess at initiator substances which may oprate most effectively upon cervical tissue. The virus is a favorite choice, and it fits the model in that dormancy is exacted. Im plantation of a particle carrying DNA can occur during adoles cence when maximal growth and cellular division take place, and when there is greatest likelihood that it will enter into an active cell or cells during replicative processes. This possibility =14.8; (5 df) all classes =11.5, (5 df) all classes diminishes as growth and secretion subside after adolescence and (1df) P = 0.01; X2 (1df) P = 0.04; X! dividing cells are less available for alteration during replication. 5.5,P 5 or more = 6.5,P 5 or more = Affected cells are now quiescent until the end of latency when = 0.02; more preg = 0.01; more deliv promotion takes place, ))erhaps in the presence of an activating nancies for patients.DeliveriesPatients(N eries for patients. cocarcinogen. Alternatively, loss of normal inhibitors, perhaps immunologie and genetically determined, may permit tumor permanent alteration of DNA, as many seem to believe, or an growth to begin after latency. The agent also may be purely chemical, a carcinogen of vary irreversible cellular impairment leading to endless and aberra ing degree contributed during coitus. The obvious choice would tional mitosis, then the modification of DNA or of the mitotic mechanism can take place either during a single coital act by the be a heavy metallic ion picked up as a byproduct of ordinary contamination from an unhygienic man. Such a metallic poison contribution of DNA which somehow changes nucleotide se might be more probable than a carcinogenic hydrocarbon, since quence, or by changes in the replication of other cellular com ponents. The alternative that several or many coital acts also such hydrocarbons do not have ready access to the cervix, except can accomplish this by increasing the probability that 1 or more in douches or contraceptives, or delivered systemically from destined cells will be initiated into first stages of oncogenesis is tobacco. There is no direct evidence that a virus-Hke particle is involved inescapable, and just as feasible. Perhaps both are possible: the single sufficient initiating dose applied during a time of cellular in cervical carcinogenesis, but there is a large body of evidence activity to a highly susceptible genotype, or the continuous from laboratory animals and from epidemiologie studies with application of smaller but effective doses to the female who also humans that chemical poisons can induce malignancy. is an allelic susceptible in a lesser quantitative degree. Other possible agents are found in the ejaculate, and in male 614
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Adolescent Coitus and Cervical Cancer

smegma. Reid (19) has associated phaging activity of cervical tissue cell aggregations with availability of postcoital sperma tozoa as a mutagen source to the genome of these cells, via nucleic acid synthesis. Where contraception is widely practiced, as in the United States, this is not a highly probable alternative, but it remains as a source of possible change. Except for experiments where smegma from animals and from humans was applied to mice, with an ensuing doubtful range of lesions, there is little to demonstrate convincingly that smegma is carcinogenic in humans. The nature of the agent, agents, or initiators still is unresolved and the most useful direction at this stage would be to search for such incriminating vectors. Other Related Variables. Several statistically significant variables are shown in this paper, some relatively strong, and others only borderline and suggestive. These data represent con nected segments of the total multidimensional study. It is espe cially true of surveys with many variables that one must ex amine accumulations of promising factors with caution, assessing those which hang together for soundness on an actual, physio logic, rational, or conjectural level. Sexual frequencies were taken by estimating greatest sustained rates for individual women at any time of life. The data cer tainly do not provide adequate reason for entertaining sexual frequency as an important variable with regard to increased risk of cervical cancer. Seeming differences for gravidity and parity between patients and controls are not strong compared to other variables, and in any case certainly are conditioned by the earlier ages at which patients began coitus. The growing number of illegitimate births in young age groups suggests a degree of correlation between youthful sexual activity and pregnancy. A single sexual act is sufficient for a conception, and the rather weak excess of patient pregnancies might be wiped out without the earlier age of coital onset for this group. Presentation of these additional variables requires exploration of the belief held by some that intimate sexual data is difficult or im|x)ssible to obtain. The method of intensive interview by qualified interviewers is, on the contrary, highly effective for obtaining valid retrosjjective sexual material, much of which is so factual that it can be compared with laboratory material for strength. It is hardly likely that any woman would forget, over look, or tend to report inaccurately the age at which she sur rendered her virginity. Nor is it reasonable to suppose that any woman would not know that she is, or is not, a virgin. It is not difficult to establish that a woman has had premarital coitus, the age of her first marriage, her total number of marriages, accurate parity and gravidity information, and, since most women have experienced few sexual partners, an accurate ap praisal of these coital contacts. Admittedly, circumcision data are much less reliable, but with the exclusion of doubtful mate rial, plus the use of pictorial devices and the realization that a control study depends upon comparisons between populations, the usefulness of such material can be examined according to intent and application rather than as an exercise in the deter mination of absolute frequencies. Since absence of circumcision on the part of any coital partner creates the possibility of contamination, the discriminating com parison is of those women who cohabited only with circumcised men. When frequencies of patients and controls in this class are
APRIL 1967

studied, fewer patients have been exposed only to circumcised coital mates. This suggests that more patients were exposed to an unknown agent which could interact with cancer suscepti bility. Circumcision of the first mate relates more directly to the period of adolescence and here the level of significance becomes borderline. But the trend still is in favor of fewer patients with first coital mates who were circumcised. In holding circumcision constant, and testing the variability of age at first coitus, results indicate that significance levels do not vary greatly for differences in age at first coitus between pa tients and controls whether they were exposed to only circum cised men or to men who were not circumcised. From this study, the variable, age at first coitus, is independent of circumcision. However, since absence of circumcision for some men amounts to an unhygienic situation, there still is reason to regard it as an additional preventive measure. Circumcision taken alone cannot be considered a primary variable that operates strongly upon risk, although lack of circumcision appears to bear some rela tionship as a peripheral supporting event. Analysis of Latency. There is some supjwrt for the notion that onset of coitus may be the time at which cancer begins, with a mean latency of about 30 years and culminating in a modal cancer frequency between ages 45 and 50. If true, decreasing age-adjusted incidence rates after menopause may be directly related to adolescent susceptibility, and not a function of menopausal change, as is sometimes held, except as menopausalassociated events may be activators of initiated cells. More accurate resolution of latency is required, but probably will not be jiossible until some of the results from this and other epi demiologie studies are used to design laboratory followup programs. Oncogenesis. It is beyond my purpose and preparation at this time to speculate uixm origins of neoplasia on cellular levels. Still, references made in this paper to initiation and promotion of cervical cancer admittedly were inspired by multistage models. If certain assumptions inherent in these models are accepted, interesting parallels may be drawn sequentially and in some de tail between concepts of an agent contributed to the human cervix via coitus during adolescence, subsequent latency, and eventual neoplasia (host-agent-donor hypothesis) and the notion of at least two stages (or a causal continuum) for oncogenesis. The design of human studies seldom is suitable for such a com parison, although Armitage and Doll (1) were able to fix defin able [joints in time for known adequate and repeated doses of radiation which could be taken as initiating carcinogenic events. It is possible that the emergence of adolescent coitus as a pivotal variable in human cervical cancer may be served by some such multistage speculation. Events may be conformed to a multistage sequence as follows: 1. Adolescence is the period of cellular activity during which initiation is most probable. This may be extended to preadolescence, but coitus seldom takes place at this time. 2. Coitus during adolescence contributes a carcinogen (first stage) which operates upon cells preferentially disposed to alteration. 3. If the dose of initiator is adequate during an act of coitus, there is a fixed probability that first changes (mutants?) will arise, progressing ]X'rhaps into dysplasias or in situ lesions.
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I.D.

Rotkin
Segi and Kurihara (23) show a low rate of uterine cancer in Ireland. This may be ascribable to religious inhibitions against casual sexual intercourse, and/or the effect of late marriage for economic reasons. The several studies of African populations show that cervical cancer is prevalent among peoples of Johannes burg (8, 16), Uganda (5), and elsewhere, and comparable to United States Caucasians in Lourenco Marques (17). Higginson and Oettle (8), Prates and Torres (17), and others presume early coitus as a general rule in some African population segments. Habibi (7) cites early marriage with relation to the high rate of cervical cancer in Iran. She et al. (24) describe 5 studies of popu lations in China, all showing significantly more early marriage and early first delivery among cervical cancer patients. Unfortu nately, age at first coitus was omitted as a variable. The high rates of cervical cancer in some South American countries might appear to go hand in hand with early onset of coitus which is supposed to be prevalent among the peoples of Peru, Chile, Colombia, and Bolivia. This may also hold for Mexican jiopulations (22). The Jewish population, with the lowest cervical carcinoma rates in the world, poses a different and more complicated prob lem. Although Jewish women may today tend to marry at later ages than surrounding populations, orthodox Jewish sub)] illa tions in the past considered age 13 as the ritual entrance into adulthood. Marriages which were pledged between children are presumed to have been consummated shortly thereafter, and one must rely heavily upon the establishment of genetic resist ance to cervical cancer either by inbreeding or by genetic drift to account for very low susceptibility by Jewish women. Lacking this susceptibility, environmental factors may be ineffective. This may be true also of the women of Ireland, where the imputa tion was isolated before emergence into the modern world. It may hold for Moslem people, where the genotype may be protective. It is interesting that circumcision is universal in the case of Jewish and Moslem people, yet Irish people did not practice circumcision until recently; and that circumcision is variable among African tribes (5, 8, 17), with high rates of cervical cancer in some tribes where circumcision takes place within an appre ciable fraction of the male population, even if delayed toward puberty. In general, it might be said that no population is known with a very high rate of cervical cancer (taken as a pro]>ortion of total female cancer) where prevalent early coitus does not hold true. Prevention and Detection. The several significant variables described in this paper are useful for immediate application to clinical practice. The recognition of a pivotal variable, age at first coitus, suggests that this information should be taken by medical practitioners for all females. The additional variables of multiple marriages, multiple coital mates, and early marriage, plus greater incidences by race and religion, afford a basis for the detection of women at risk. This pattern also is available for prevention of disease and/or advanced pathology for subpopulations where there is most likelihood of cervical cancer. There is no question but that pro grams of Papanicolaou smears among underprivileged groups is an undertaking of first urgency, and should include all nonvirgin women, married or unmarried. A formula for clinicians might be: for women who have experi enced at least 1 coital act, where coitus began during adolescence, where there was more than 1 marriage and/or 1 coital mate, CANCER RESEARCH VOL. 27

Without a second energy source (cocarcinogen) invasion will not ensue. 4. The probability that such an initiator will encounter ac tively dividing cells rises as more sexual mates are exj>erienced. Certain males carry sj>eeificcarcinogens. 5. A minimal but adequate dose of initiator can be reinforced by successive similar doses from the same sexual mate by provid ing related opportunity for one or more susceptible and active cells to become infected. Each such event is indei>endent. 6. With very small concentrations of an initiating contaminant the probability of scoring a hit ujxm a ripe (destined) cell is minimal. This is not unlike fertilization in that the destined cell (egg) is propelled into activity by the energy stimulus of sperm. 7. Particulate, chemical, or physical carcinogens are all ade quate. Viral and chemical initiators are most likely. A virus can be mutagenic; a metallic poison could justify Shubik's (25) alternative to mutation in regarding carcinogenesis as a reactive process, but his designation of the central event as cellular damage, with retained viability, is doubtful. The central event is irreversible alteration of the mitotic or replicative or divisional mechanism. Whatever causes the cell to divide has been made forever operative. 8. Latency is the interval of progression between initiation and promotion. This may be a dormancy, or a reactive continuum, the exact nature of which is unknown. 9. Promotion requires the superapplication of energy, as from a cocarcinogen, which can happen at any time after initiation. This may explain the range of latency from 8 to 61 years, with a mode of 30 years. Peaking incidence at about menopausal age simply may describe this latency mode, or may designate a period of secondary activity when a cocarcinogen is most avail able to propel prepared cells into malignancy. This may involve hormonal patterns or weakening of immunologie defenses. The data from which this simulation proceeds do not fit a single stage model unless reversible early lesions are left unexplained. A theory of linear or continuous accrual of effect upon altered tissue could be considered if each stage of a multistage theory is a perceptible discontinuous (xjint ujion the continuously develop ing neoplasm, with progression as the unknown series of events. The possibility that multidimensional influences conspire to o])erate additively ujxm tissues in the stages of initiation and progression should not be overlooked. Kotin (12) has described interaction between viruses and chemical carcinogens, applied simultaneously to strain mice, in producing neoplasia. Successive coital partners, secondary influences such as psychosexual pres sures and unknown socioeconomically related forces could co operate in directing an adequate genotype into carcinogenesis. Comparison Populations. Literature accumulating in the assessment of cervical cancer in other geographic jxjpulations should be useful in resolving the age at first coitus hyix>thesis and other variables. Unfortunately, public health workers who are rejwrting other ]x>pulations are not designing strong sexual components into their surveys. Also, other countries where rates of cervical cancer are different from the United States and Europe are not being surveyed at all. No epidemiologie research in cervical cancer can be considered adequate without a thorough evaluation of two areas: (a) full sexual information, including age at first coitus, numbers of sexual mates and supirting in formation, and (ft) accurate prevalence and incidence rates of cervical carcinoma, all with verified pathology. 616

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Adolescent Coitus and Cervical Cancer

who are derived from a non-Caucasian population and are of non-Jewish origin, risk is greatest. For prevention on population levels, educational programs may not be impossible. It is well known that the adolescent girl generally benefits little in any sense by sexual exposure, and that early coital as well as marital beginnings are disadvantageous for her from many points of view. On the other hand, threat of increased cancer risk is a negative procedure which may result in lifelong sexual trauma, and is strongly inadvisable, especially since the act of coitus in itself appears only to implement the contribution of a contami nant which is effective mostly during adolescence.
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