1 Northern California Cancer Center, Union City, CA.
2 Division of Surgical Pathology, Stanford University Medical Center, Stanford, CA.
Received for publication January 29, 2003; accepted for publication April 9, 2003.
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ABSTRACT |
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case-control studies; endometriosis; Hodgkin disease; lactation; parity
Abbreviations: Abbreviations: CI, confidence interval; OR, odds ratio; Th1, T helper cell type 1; Th2, T helper cell type 2.
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INTRODUCTION |
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MATERIALS AND METHODS |
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Controls were English-speaking women without a history of Hodgkins disease residing in the same nine-county area who were identified through random digit dialing, as described elsewhere (14). Briefly, calls were made to 12,970 random telephone numbers, yielding 830 nonanswers, 2,787 businesses or pay phones, 3,762 disconnected numbers, 945 electronic responses, 18 second telephone lines, and 4,628 residences. Among the residences, 10 percent of respondents refused to participate in the household enumeration, which targeted adult females by age and race/ethnicity; 58 percent were ineligible on the basis of sex, age, race/ethnicity, or language use; and 32 percent were eligible for future contact. From this last group, we randomly selected and attempted to recruit one woman per household as needed for frequency-matching to cases on 5-year age group and race/ethnicity.
Physicians of eligible case women were first queried about contraindications to contacting the patient. Cases without physician refusal and eligible controls were invited, initially by letter and then by telephone, to participate in the studys in-person interview. Participating subjects were required to sign a consent form before being interviewed.
The standardized interview inquired about reproductive potential (age at menarche, years from menarche to commencement of regular menses, average duration of menstrual cycles, number of menstrual periods missed (aside from pregnancies and lactation), history of and age at hysterectomy and oophorectomy, age at last menstrual period); reproductive experience (age at, duration of, and outcome of each pregnancy; duration of each associated period of nursing); gynecologic conditions (history of and age at diagnosis of endometriosis, uterine fibroids, and ovarian cysts); and use of exogenous hormones (dates and duration of each episode of use for oral contraceptives and for other hormones, including use of estrogens with or without progestins in menopause-associated hormone replacement therapy). The interview also addressed childhood and adult social class measures. All questions pertained to the year prior to diagnosis for cases and a corresponding time before interview for controls; controls were frequency-matched to cases according to this interval. Subjects completed a life events calendar to facilitate recall of study exposures (15). Thirty subjects who had moved from the area were interviewed by telephone using the same questionnaire and mailed interview materials.
The reliability of both random digit dialing enumeration and selected questionnaire responses was addressed through reinterview of a random sample of participants and was found to be good (14, 16). Potential bias resulting from the exclusion of deceased cases was evaluated using questionnaire responses obtained from the next of kin of 19 of the 38 deceased case women through a self-administered, abbreviated version of the study instrument.
Of the 370 study-eligible cases, two (<1 percent) were not contacted at their physicians request, 10 (3 percent) could not be contacted within 2 years of diagnosis (a cutoff established because of concerns about recall accuracy), two (<1 percent) had left the United States, 19 (5 percent) died before interview, five (1 percent) could not be located, 12 (3 percent) refused to participate, and 320 (87 percent) were interviewed. Among the 310 interviewed patients for whom pathology specimens were obtained, 302 (97 percent) were considered to have Hodgkins disease on histologic and/or immunohistochemical grounds, and 259 (86 percent) of these were found to have the most common histologic subtype, nodular sclerosis. Given the very low rate of disease misclassification overall, the 10 interviewed patients without pathology re-review were assumed to have Hodgkins disease. Thus, 312 cases were included in the analyses. Among the 450 women selected for recruitment as controls, 49 could not be relocated, 76 refused, and 325 (72 percent) were interviewed.
Statistical analysis
To examine case-control differences, we first compared relative frequency distributions with chi-squared or Fishers exact tests. We evaluated normally distributed continuous variables with t tests to compare mean values; we categorized data on all other variables into tertiles based on the distributions of control responses. We calculated unadjusted odds ratios and corresponding 95 percent confidence intervals to estimate relative risks. For reproductive potential, we calculated the cumulative numbers of menstrual cycles and reproductive years using age at menarche and age at the last menstrual period or in the reference year, considering cessation of menstrual periods only if it occurred at least 1 year prior to the reference year to minimize any disease-related effect on menses. For reproductive experience, we calculated the total numbers of pregnancies (gravidity), livebirths (parity), therapeutic abortions, miscarriages (20 weeks gestation), and stillbirths (>20 weeks gestation); the total numbers of months pregnant, months since last delivery, and months of nursing; and age at first full-term pregnancy. Recurrent miscarriage, evaluated among women with at least one fetal loss, was defined as two or more unexplained miscarriages because of the low prevalence of this outcome. Women were considered to have nursed if their lifetime duration of lactation was at least 1 month. For exogenous hormones, we summed periods of use to obtain total duration of exposure; long-term users were compared with both never users (data presented in the tables) and short-term users (data presented in the text). The prevalence of oophorectomy was deemed too low to warrant joint examination with age at surgery.
Analyses were first conducted among women of all ages for evaluation of the overall effects of risk factors and for consistency with prior studies (1721). Because of age-specific variation in male-female incidence rate differences (figure 1), the strong association of age with some reproductive characteristics (e.g., parity, hormone replacement therapy), and our prior findings of age-specific variation in social class risk factors (10, 11), we also examined case-control differences separately in women aged 1934, 3554, and 5579 years after recategorizing continuous variables and social class indicators into tertiles based on age-specific distributions of control responses.
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RESULTS |
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Distributions of selected study variables among cases and controls are shown in table 1. For reproductive potential, there were no case-control differences in the indicators shown or in average age at menarche (12.8 years vs. 13.0 years, p = 0.22), average duration of the menstrual cycle (28.4 days vs. 28.7 days, p = 0.25), proportion of subjects who had missed more than six menstrual periods (8.3 percent vs. 8.6 percent, p = 0.89), or, among postmenopausal women, average age at the last menstrual period (42.7 years vs. 45.0 years, p = 0.16). Similar proportions of cases and controls reported reproductive surgery (9 percent vs. 11 percent (p = 0.63) for hysterectomy; 4 percent vs. 5 percent (p = 0.40) for oophorectomy), but cases were somewhat younger than controls at surgery (mean age at oophorectomy, 39.6 years vs. 46.7 years (p = 0.05); mean age at hysterectomy, 38.8 years vs. 42.6 years (p = 0.11)).
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Uterine fibroids were reported by slightly fewer cases than controls, but endometriosis and ovarian cysts were not associated with Hodgkins disease risk. The highest tertile of cumulative oral contraceptive use (5.3 years) was suggestively linked with lower disease risk in comparison with the lowest tertile of use (<2.2 years) (unadjusted OR = 0.6, 95 percent CI: 0.4, 1.0). Cases were less likely than controls to have ever used hormone replacement therapy (9.9 percent vs. 15.1 percent, p = 0.05; OR = 0.6, 95 percent CI: 0.4, 1.0), and longer-term users were at approximately half the Hodgkins disease risk of short-term users (OR = 0.7, 95 percent CI: 0.4, 1.0).
In multivariate analyses (table 1), parity was not associated with Hodgkins disease among women who had nursed. Among never-nursing women, those with three or more births were suggested to have an elevated risk of Hodgkins disease in comparison with nulliparous women. Women who had had two or more miscarriages had a nearly threefold higher risk of Hodgkins disease than women with one miscarriage. Marginally protective effects remained for a history of uterine fibroids and for long-term use of oral contraceptives as compared with short-term use (for 5.3 years of use vs. <2.2 years, adjusted OR = 0.7, 95 percent CI: 0.4, 1.0) but not for long-term use of hormone replacement therapy versus short-term use (adjusted OR = 0.5, 95 percent CI: 0.1, 1.6).
Table 2 presents relative frequency distributions and odds ratios for cases and controls aged 1934, 3554, and 5579 years for variables associated with Hodgkins disease risk in at least one of the age groups. For women aged 1934 years, recurrent miscarriage was linked to elevated risk of Hodgkins disease, although confidence intervals around the adjusted odds ratios were wide, and endometriosis was suggestively associated with a reduced risk of Hodgkins disease after adjustment for confounders. Among women aged 3554 years, cases were half as likely as controls to have nursed, but this association appeared to vary with parity (for one birth, unadjusted OR = 2.6, 95 percent CI: 0.3, 26.1; for two births, OR = 0.5, 95 percent CI: 0.2, 1.4; for three or more births, OR = 0.2, 95 percent CI: 0.0, 1.1). In multivariate analysis, ever nursing seemed to be protective regardless of parity. Among never-nursing women, those with one child also had a substantially lower risk of Hodgkins disease than nulliparous women, but those with higher parity appeared to have an elevated risk. Recurrent miscarriage remained a significant predictor of Hodgkins disease risk. Longer-term hormone use was associated with lower Hodgkins disease risk, suggestively for oral contraceptives in comparison with shorter-term use (adjusted OR = 0.5, 95 percent CI: 0.2, 1.2) and significantly for hormone replacement therapy in comparison with no use. For both of these age groups, findings were quite similar among the 169 and 70 nodular sclerosis cases (comprising 87 percent and 86 percent of all cases aged 1934 years and 3554 years, respectively) compared with their respective controls (data not shown).
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DISCUSSION |
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In women aged 3554 years, the effect of parity was modified by nursing, such that higher parity appeared to be associated with increased Hodgkins disease risk among never-nursing women, while nursing appeared to decrease risk irrespective of parity. Since, to our knowledge, no previous studies of Hodgkins disease risk have examined nursing, an associated protective effect could explain some of the lower disease risk reported for parity (19, 25, 26), and the variation in parity effect estimates across studies could reflect differences in the population prevalences of nursing. However, such confounding could only explain the inverse association of parity and Hodgkins disease risk (18, 24, 25) if a nursing effect were cumulative, which it was not in our data but recently was found to be in a study of non-Hodgkins lymphoma (27). Among women aged 3554 years, Hodgkins disease risk also was significantly elevated with recurrent miscarriage and diminished with hormone use.
For women over age 54 years, Hodgkins disease risk was suggestively associated only with irregular menses, endometriosis, and hormone use. Analyses for this age group were hampered by the small sample size, which was consistent with Hodgkins disease incidence patterns and with the low interview rate (53 percent of all Hodgkins disease patients over age 54 years) due to mortality, although inclusion of next-of-kin data for 12 of the 21 deceased older cases produced no marked changes in associations beyond a stronger effect of oral contraceptive use (OR = 0.3, 95 percent CI: 0.1, 0.8). In addition, data were missing for 9 percent of older subjects as compared with 0.1 percent of women aged 3554 years, and older cases are more heterogeneous in terms of tumor histologic types, which exhibit distinctive epidemiologic patterns (28).
In general, our data are consistent with some effect of steroid hormones or other hormones on the development of Hodgkins disease. A protective role of higher levels of hormone exposure is suggested by most of our findings, including reduced risks with parity, nursing, and exogenous hormone use, a marginally reduced risk with uterine fibroids (whose growth is driven by steroid hormones (29)), and increased risk with younger age at reproductive surgery (which involves loss of hormone production). Because lymphocytes are thought not to exhibit hormone receptors (30), this protective influence probably operates indirectly through the well-established effects of estrogens, progesterone, and other hormones on immune function. Although their precise immunologic effects remain poorly understood, estrogen, progesterone, and prolactin have been noted to influence regulation of T helper cell type 1 (Th1) and T helper cell type 2 (Th2) cytokine production and lymphopoiesis (31). Physiologic changes associated with several study exposures (increases in circulating estrogens and progesterone seen during pregnancy, in laboratory and animal studies (3134), and with use of oral contraceptives and hormone replacement therapy (31, 35, 36); prolactin increases seen during nursing (37); and immunologic changes associated with endometriosis (29, 38)) have also been associated with changes in the relative predominance of Th1/Th2 cytokines, reductions in the number of natural killer cells, and inhibition of B-cell production (32, 34, 39). In addition, nursing elevates levels of parathyroid hormone-related protein, which has been shown to suppress the growth of lymphocyte cell lines infected with human T-cell lymphotropic virus type 1 (40, 41). Recurrent miscarriage is characterized by elevated levels of natural killer cell activity (29), consistent with the elevation of Hodgkins disease risk that we found for this factor. Thus, steroid hormones and other hormones may affect development of Hodgkins disease, now thought to be a B-cell lymphoma, through their impact on B-cell production. Postmenopausal use of exogenous hormones may reduce risk of intermediate or high-grade non-Hodgkins lymphoma by suppressing production of interleukin-6, a Th2 cytokine known to act as a paracrine growth factor for lymphoma (42). However, use of hormone replacement therapy was recently associated with increased risk of follicular lymphoma (43).
Some of our findings for parity are inconsistent with a suppressive effect of hormones on lymphomagenesis. Among women aged 3554 years, the limitation of lower Hodgkins disease risk associated with childbearing to a parity of 1 is puzzling, as is the increased risk for higher parity. Only one prior study noted an increase in Hodgkins disease risk with parity, and it did not report any protective influence of low parity (17). Given the accumulated epidemiologic evidence for an inverse association of Hodgkins disease with number of births (table 3) and the absence of selection bias for our controls aged 3554 years, this effect of parity on Hodgkins disease risk in our population may be a chance finding. An alternative explanation involves social correlates of parity (6, 24). Hodgkins disease risk in young adults has been linked to childhood infection delayed until adolescence (6). Among women under age 45 years in our study, those from smaller childhood households (a proxy for less early contact with children and thus delayed infection exposure) were at four times the Hodgkins disease risk (adjusted OR = 4.0, 95 percent CI: 1.3, 12.9) of those from larger childhood households if they also had had two or more births (10). Thus, among women not otherwise protected from Hodgkins disease development by nursing, an elevated Hodgkins disease risk with higher levels of parity could reflect an overriding consequence of late exposure to infection via their offspring. Small sample size prevented a test of this hypothesis in our data.
Some of our study findings are also consistent with nonhormonal mechanisms of Hodgkins disease risk. Recurrent miscarriage, associated with a substantially elevated risk of Hodgkins disease in women under age 55 years, has been associated with certain human leukocyte antigen class II alleles and haplotypes (44, 45), as has risk for the nodular sclerosis histologic subtype of Hodgkins disease, which comprised the majority of our cases under age 55 (5, 46). Thus, recurrent miscarriage and Hodgkins disease could be related partly through a common genetic susceptibility, and the absence of an association between miscarriage and Hodgkins disease in older women could reflect the much lower prevalence of the nodular sclerosis subtype in these women. Endometriosis, which affected Hodgkins disease risk in an age-modified pattern, manifests differently in younger and older women in terms of clinical presentation and other features (4749), suggesting differences in etiology by age. The protective effect of endometriosis on Hodgkins disease risk among younger women in our study is consistent with its associated changes in immune function (29, 38). Endometriosis also is associated with low parity, hormone treatment, family aggregation, and, in one small study, infectious mononucleosisall risk factors for Hodgkins disease (50)but its persistent association with Hodgkins disease risk in our multivariate analysis makes confounding an unlikely explanation.
Finally, our findings may have been affected by error. Because all patient information was self-reported, its validity is uncertain, although the reliability of responses to questions on reproductive experience was very good ( = 0.650.94) (16). For medical conditions with diagnostic imprecision (e.g., endometriosis), some misclassification probably occurred, but the similar mean years of education for cases (14.1 years) and controls (14.3 years) would tend to rule out differential misreporting based on medical access or knowledge. While recall bias is also a possibility, the opposing associations for miscarriage and endometriosis make this a less likely explanation for our findings. In some subgroups, the small numbers of subjects produced unstable odds ratios, and the low parity of our population limited our statistical power to detect effects that might be apparent only with higher-order births (25). Finally, we cannot rule out the possibility that our findings are due to uncontrolled social correlates of reproductive experience rather than to hormonal effects.
On balance, our population-based examination of a range of reproductive and related factors supports the possibility of a transient effect of steroid hormones and other hormones on the development of Hodgkins disease in women. Given the established if incompletely understood interaction between hormones and immune function, additional exploration of this understudied aspect of Hodgkins disease etiology in a larger population could be informative.
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ACKNOWLEDGMENTS |
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The authors thank Barbara Dabney, Janet Kettlehut, Virginia Zemlin, Marta Zahn, Rita Leung, Dr. Susan Stewart, Alice Dantsuka, and Connie Cady for their contributions to this project.
The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services or the California Department of Health Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US government or the state of California.
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NOTES |
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REFERENCES |
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