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American Journal of Epidemiology Advance Access originally published online on June 10, 2008
American Journal of Epidemiology 2008 168(3):278-288; doi:10.1093/aje/kwn119
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American Journal of Epidemiology Published by the Johns Hopkins Bloomberg School of Public Health 2008.

ORIGINAL CONTRIBUTIONS

Non-Hodgkin Lymphoma in Women: Reproductive Factors and Exogenous Hormone Use

Jennifer S. Lee1,2, Paige M. Bracci3 and Elizabeth A. Holly2,3

1 Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, Department of Internal Medicine, University of California Davis, Sacramento, CA
2 Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA
3 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA

Correspondence to Dr. Paige M. Bracci, Department of Epidemiology and Biostatistics, University of California San Francisco, 3333 California Street, Suite 280, San Francisco, CA 94118-1944.

Received for publication October 17, 2007. Accepted for publication April 7, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Few studies of reproductive hormone exposures and non-Hodgkin lymphoma (NHL) have examined NHL subtypes. Associations between reproductive hormonal factors and risk of all NHL and of two predominant subtypes, diffuse large-cell lymphoma (DLCL) (n = 233) and follicular lymphoma (n = 173), were investigated among women (n = 581) in a large, population-based, case-control study (1,591 cases, 2,515 controls). Controls (n = 836) identified by random digit dialing were frequency matched by age and county to incident NHL cases ascertained in the San Francisco Bay Area of California in 1988–1993. Adjusted unconditional logistic regression was used to obtain odds ratios. More than four pregnancies indicated a possible lower risk of all NHL (odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.55, 1.2; p-trend = 0.06) and of DLCL (OR = 0.53, 95% CI: 0.31, 0.90; p-trend = 0.01). Exclusive use of menopausal hormone therapy for ≥5 years was associated with a reduced risk of all NHL (OR = 0.68, 95% CI: 0.48, 0.98) and of DLCL (OR = 0.50, 95% CI: 0.30, 0.85). Oral contraceptive use indicated a lower risk of all NHL (OR = 0.68, 95% CI: 0.49, 0.94), and perhaps DLCL (OR = 0.79, 95% CI: 0.51, 1.2), and of follicular lymphoma (OR = 0.75, 95% CI: 0.46, 1.2). Results suggest that endogenous and exogenous reproductive hormones confer different risks by NHL subtype and are associated with a reduced risk of DLCL in women.

case-control studies; contraception; estrogens; hormone replacement therapy; lymphoma, non-Hodgkin; menopause; pregnancy; reproduction

Abbreviations: DLCL, diffuse large-cell lymphoma; HT, menopausal hormone therapy; NHL, non-Hodgkin lymphoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The incidence of non-Hodgkin lymphoma (NHL) is increasing, while determinants in the pathogenesis remain unclear (1). NHL comprises a complex and heterogeneous set of lymphoma subtypes that are likely to differ etiologically, ranging from indolent follicular lymphoma to aggressive diffuse large-cell lymphoma (DLCL). Compared with men, women have a 30 percent lower overall incidence of NHL. However, sex differences in incidence across NHL subtypes exist; women have a lower incidence of DLCL and a comparable incidence of follicular lymphoma (2). Estrogen and other reproductive hormone exposures may confer a reduced risk of some NHL subtypes such as DLCL in women by influencing the immune system via numerous mechanisms (3). For example, estrogen and other reproductive hormones mediate immune responses, release of relevant cytokines, B-cell differentiation and proliferation, and multiple stages of lymphomagenesis (4–8).

Reproductive hormone exposures in women include menstrual factors, pregnancy, and use of exogenous hormones such as oral contraceptives and menopausal hormone therapy (HT). Prior reports are mixed about the relation between these hormonal factors in women and the risk of NHL, and few studies have explored whether such inconsistent findings are due, at least in part, to the heterogeneity among NHL subtypes (3, 9, 10). In our earlier analyses restricted to White non-Hispanic women, several variants in genes involved in reproductive hormone metabolism were associated with NHL in the subset of women for whom DNA was available; the corresponding exposure data showed a decreased risk of NHL associated with ever use of oral contraceptives or of non-oral-contraceptive hormones (11).

Here, we present results from more detailed analyses of the risk of NHL and common NHL subtypes associated with reproductive factors and use of exogenous female hormones among all women in our population-based case-control study in the San Francisco Bay Area of California.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
There were 1,591 eligible cases and 2,515 eligible controls who were interviewed in a large, population-based, case-control study of NHL in the San Francisco Bay Area. Eligibility criteria for incident NHL cases identified by the Northern California Cancer Center's rapid case ascertainment system were 1) diagnosis between 1988 and 1993, 2) aged 21–74 years, 3) a resident of one of six Bay Area counties at diagnosis, 4) no physician-indicated contraindications to contact, and 5) able to complete an interview in English. Controls were identified by random digit dialing and were frequency matched to cases by 5-year age group, sex, and county of residence. Eligibility criteria for controls were the same as those for cases with the exception of NHL diagnosis. No proxy interviews were conducted. Results from our earlier analyses showed that noninterviewed NHL cases were younger, more likely to be homosexual men infected with human immunodeficiency virus, and more likely to have high-grade and not-otherwise-specified NHL (12). Response rates were 72 percent for eligible cases and 78 percent for eligible controls. Information collected from the 1,417 women study participants (581 cases, 836 controls) was used in these analyses.

Diagnostic pathology slides were rereviewed and classified by using the working formulation for 97 percent of NHL patients. To reflect the more recent Revised European American Lymphoma Classification (REAL)/World Health Organization classification system, diffuse large-cell and large-cell immunoblastic subtypes were combined to represent DLCL, and all follicular subtypes were combined to represent follicular lymphoma for these analyses (13).

All participants provided informed consent prior to interview and venipuncture. Procedures and protocols were approved by the University of California San Francisco Committee on Human Research. Further details of the study design and methods have been published in previous manuscripts (12, 14–20).

Interviews
Trained interviewers used a standard questionnaire to collect exposure and risk factor data from study participants during in-person interviews. Interviews were conducted at a place and time convenient to participants, with most taking place in participants' homes. Data collected included demographic characteristics, personal and family medical histories, travel and other lifestyle factors, occupational history, and chemical exposures.

Participants also were asked about reproductive history and use of exogenous hormones. Reproductive history questions included age at menarche, number of pregnancies, number of births, sex of each child in birth order, and age at birth of the first child. Questions on exogenous hormone use pertained to the use of oral contraceptives and of other non-oral-contraceptive hormones. For oral contraceptive use, women were asked whether they had ever used birth control pills, the total number of months and years they were used, the brand(s) used (assisted by photographs and cue cards), age at which they were first used, and duration of use for each type. Data were similarly collected for use of non-oral-contraceptive hormones, primarily HT, and hormones to inhibit lactation or to treat morning sickness.

Statistical analyses
All statistical analyses for women (581 cases, 836 controls) were conducted by using SAS v.9 software (SAS Institute, Inc., Cary, North Carolina). Odds ratios and 95 percent confidence intervals were computed as estimates of relative risks (hereafter called risk) using unconditional logistic regression adjusted for age group. For analyses of exogenous hormone use, women who never had used any exogenous hormones constituted the referent group. Duration of hormone use was computed for oral contraceptive use only, HT use only, and any exogenous hormone use. Duration was categorized as <1 year, 1–<5 years, 5–<10 years, and ≥10 years of use for easy comparison with published data on exogenous hormone use. Time since first and last use was computed as the difference between age at first (or last) use and age at diagnosis (or interview for controls). Continuous variables, other than duration of use, were grouped on the basis of quartiles of the frequency distribution among controls. If the odds ratios for contiguous categories of a factor were not different from one another or if cell numbers were small, these categories were collapsed for the final analyses.

Information on age at menopause was not collected in the study questionnaire. However, analyses that used average age at menopause for US women (age 51 years (21)) showed results for HT use to be similar for postmenopausal women and all women. Therefore, data for all women are presented in the tables in this article. Oral contraceptive use was dichotomized as first use before 1970 versus 1970 or later to assess the effect of the highest-dose-estrogen oral contraceptives prescribed prior to recommendations resulting from the 1970 US Senate hearings (http://www.fda.gov/bbs/topics/CONSUMER/CON00027.html). We also chose this cutpoint for comparability with already published studies of oral contraceptive use and risk of NHL (9, 22).

Factors considered in the analyses as potential confounders or effect modifiers included race, marital status, years of education, lifetime average number of alcoholic drinks consumed per week, lifetime number of sexual partners, and obesity (based on usual adult weight, body mass index (weight (kg)/height (m)2) ≥30) (16). Potential confounding factors were retained in the final models if their inclusion modified the main effect estimate by more than 10 percent. Linear trends in odds ratios were determined from adjusted unconditional logistic models and were based on the beta estimate for the factor of interest when included in the model as an ordinal variable. When appropriate, p values for linear trend are presented here.

All statistical tests were two sided and were considered significant for p ≤ 0.05 (p ≤ 0.10 for interaction). Results were considered borderline significant for p > 0.05 to p ≤ 0.10.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Median age at diagnosis or interview for both cases and controls was 61 years (interquartile range, 19). Lifestyle factors associated with disease status that also may be associated with reproductive hormone exposures included educational level, weekly alcohol consumption, body mass index, marital status, and lifetime number of sexual partners (table 1).


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  		TABLE 1. Lifestyle and demographic characteristics of women with non-Hodgkin lymphoma and of controls participating in a population-based case-control study, San Francisco Bay Area, California, 1988–1993

 
Reproductive factors
Menstrual and pregnancy factors were not consistently associated with risks of all NHL (table 2). However, an increasing number of pregnancies (p-trend = 0.01) and of livebirths (p-trend = 0.04) were associated with a decreasing trend in the risk of DLCL (table 2). Sex of the first child, total number of boys, total number of girls, and percentage of boys relative to family size were not associated with NHL risk (data not shown in table, p > 0.24 for all factors).


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  		TABLE 2. Age-adjusted odds ratios and 95% confidence intervals for reproductive factors associated with all non-Hodgkin lymphoma and with the subtypes follicular lymphoma and diffuse large-cell lymphoma among women in a population-based case-control study, San Francisco Bay Area, California, 1988–1993

 
Exogenous hormone use
Approximately 70 percent of women with NHL had ever used oral contraceptives, HT, or other hormones (table 3). Slightly more NHL patients had ever used HT alone, whereas fewer women with NHL, compared with controls, had ever used oral contraceptives alone (table 3). Among women who had used HT alone, 13 percent had used oral estrogen plus progestin and 55 percent had used oral estrogen alone. The remainder of these women had used menopausal hormones administered by injection, cream, or patch. One percent of women reported having used other hormones to inhibit lactation, to treat menstrual disorders, or to treat morning sickness as their only exogenous hormone exposure.


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  		TABLE 3. Odds ratios and 95% confidence intervals for exogenous hormone use* associated with all non-Hodgkin lymphoma among women in a population-based case-control study, San Francisco Bay Area, California, 1988–1993{dagger}

 
The observed decreased risk of all NHL with exogenous hormone use was found for mainly those women who had used oral contraceptives. In models adjusted for age group and total years of oral contraceptive use, increasing number of years since first use of oral contraceptives was associated with a reduced risk of all NHL (p-trend = 0.005, table 3). First oral contraceptive use before 1970 also was associated with a lower risk (p-trend = 0.03), although, after adjustment for age group, age at first use, duration of use, and lifetime number of sexual partners, individual confidence intervals included unity. Analyses of types of hormones by NHL subtype suggested that oral contraceptive use was associated with a reduced risk of DLCL and follicular lymphoma, although the associations did not differ from chance (table 4). Analyses by first use before 1970 versus 1970 or later showed a decreasing trend in odds ratios with earlier use for risk of DLCL (p-trend = 0.02), although individual effects were not different from unity (table 4). No associations were observed for follicular lymphoma risk.


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  		TABLE 4. Odds ratios and 95% confidence intervals for exogenous hormone use* associated with follicular lymphoma and diffuse large-cell lymphoma among women in a population-based case-control study, San Francisco Bay Area, California, 1988–1993{dagger}

 
A decreasing trend in NHL risk was observed with increasing total years of use of HT (table 3, p-trend = 0.05). When analyses were restricted to women who used HT alone, those who reported 5 or more total years of use had a reduced NHL risk, although there was little evidence of a linear trend in risk (p-trend = 0.09). Further analyses of total years of use and years since last use of HT combined showed that recent long-term users of HT had a nearly 40 percent reduced risk of NHL compared with women who had never used exogenous hormones (table 3). An association was suggested between long-term and more recent use of HT and risk of all NHL and of DLCL (tables 3 and 4). A decreasing risk of DLCL was associated with older age at last use of HT, with more recent use, and with longer duration of use for women who used HT exclusively (table 4). Risk estimates for follicular lymphoma by characteristics of HT use appeared to differ somewhat from those for DLCL, but confidence intervals were wide. Results did not differ by type of HT for the relatively few women who used estrogen alone or who used estrogen plus progestin.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
This study focused on whether reproductive factors among women and exogenous hormone use are related to risk of NHL and of its common subtypes, DLCL and follicular lymphoma. Our results are consistent with data showing that follicular lymphoma incidence is similar in women and men, whereas DLCL is more common in men. Results indicate that greater exposure to female reproductive hormones, particularly from multiple pregnancies and exogenous hormones, may be associated with a reduced risk of NHL, particularly DLCL. Such exposure to estrogen and/or other reproductive hormones may alter immunity and hinder the development of NHL in women.

Inconsistent results have been reported in previously published investigations of the association between exposure to reproductive hormones and risk of NHL in women (23). In most studies, with a few exceptions (3, 9, 10, 22, 24), pooling heterogeneous NHL subtypes likely contributed to the observed inconsistencies in risk estimates. Consistent with several earlier reports (3, 24), we found that risk of NHL was somewhat decreased with increasing parity and was not associated with age at menarche (3, 24) or women's age at the birth of their first child (3, 9, 24–26).

Also similar to several prior reports (9, 10, 22, 27–29), the current results provided some evidence of an inverse relation between HT use and NHL, particularly DLCL. In contrast, we found no consistent association between duration of HT use and follicular lymphoma risk, whereas, in the Iowa Women's Health Study, long-term HT use was associated with an increased risk of follicular lymphoma (10). From our results, higher-dose oral contraceptives may be associated with a decreased risk of NHL, particularly DLCL, possibly accounting for the similar relation for all NHL cases. The relation between oral contraceptive use and follicular lymphoma risk was less clear in this study because of the relatively small number of follicular lymphoma cases. With regard to the use of oral contraceptives, our results are most consistent with those from a Los Angeles, California, study of women with aggressive intermediate and high-grade NHL, where NHL risk was decreased among women who had ever used oral contraceptives, had used oral contraceptives for 5 years or more, or had used oral contraceptives before 1970 (9). Similar results for ever use of oral contraceptives and with pre–1970 use also have been observed in some (1, 9, 22, 30) but not all (28, 31) studies that evaluated exogenous hormone use among women.

Greater exposure to reproductive hormones during several pregnancies and exogenous hormone use may reduce the risk of NHL by altering several facets of immunity. These include modulating cell-mediated immune (Th1) and antibody-mediated immune (Th2) responses, Th1 and Th2 cytokine production, B-cell lymphopoiesis and survival, and immune cell apoptosis (7). Greater estrogen and progesterone exposures lead to a reduction in B-cell lymphopoiesis, whereas ovariectomy enhances lymphopoiesis (32–34). Early B-cell precursors appear particularly sensitive to sex steroids, such as estrogen, resulting in decreases in B-cell differentiation and proliferation (5). Oral contraceptives also might reduce lymphomagenesis by altering circulating lymphocytes, including B-cells, and proportions of lymphocyte subsets throughout cycles of oral contraceptive use (35).

Pregnancy represents a complex hormonal state in which nearly every aspect of immune response is modified (36), including sharp increases in estrogen and progesterone, changes in levels of cytokines and growth factors, and modulation of immune cell counts and functions. Estrogen likely has biphasic dose effects; lower levels may enhance, whereas higher levels, such as during pregnancy, may inhibit specific immune activities. These effects are evident in pregnant women with immune disorders, such as lupus and rheumatoid arthritis (37). For example, lupus tends to be predominantly a Th2 response that antagonizes Th1 cells, and lupus tends to flare during pregnancy likely from high estrogen and progesterone levels exacerbating this shift in immune balance (37). In contrast, rheumatoid arthritis tends to be predominantly a Th1 response, and symptoms diminish during pregnancy. Repeated exposure to high levels of estrogen and other reproductive hormones in highly parous women may tip the balance of immune responses to reduce the risk of developing DLCL (7, 37, 38).

To our knowledge, results that showed a reduced NHL risk for recent long-term users of HT are unique to this study and imply a possible detrimental effect of HT on lymphomagenesis. HT may restore Th1/Th2 balance during menopause to reduce NHL risk (39, 40). HT may prevent the menopausal changes in levels of cytokines, such as interleukin-10 (8, 41). It also may lower natural killer cell activity (40) and restore premenopausal proportions of certain subsets of B-cells (42). HT prevents the menopausal increase in interleukin-10, a cytokine that is elevated in NHL patients and is considered a pathogenic factor in NHL. Interleukin-10 suppresses Th1 cytokines and appears to act as an autocrine growth factor that potently stimulates B-cell proliferation and differentiation in B-cell lymphomas (43). Moreover, polymorphisms in the interleukin-10 gene may be associated with NHL risk (44). Interleukin-6 also has garnered much attention, particularly as a potent growth factor cytokine prominent in DLCL and other lymphomas (45). Menopausal estrogen deprivation appears to enhance interleukin-6 production by peripheral blood monocytes (45, 46). Using estradiol also appears to lower interleukin-6 levels substantially in postmenopausal women, compared with premenopausal women or to untreated postmenopausal women (45–47), and may contribute to reduced NHL risk.

The complex interactions among female reproductive hormones, immunity, and lymphomagenesis are not well understood. By distinguishing NHL phenotypes, the modulating effects of reproductive hormones of various doses, duration, timing, and type can be better ascertained (8). New molecular techniques such as gene expression assays are being used to recognize gene expression signatures for the many NHL entities (48, 49) and thus may help to differentiate the subtypes affected by reproductive hormones.

Limitations of the current study need to be considered when interpreting these results. Case-control studies are prone to recall bias and misclassification of exposure data; however, in the current study, recall bias was less likely because most risk factors for NHL are unknown to the general public. To minimize potential biases, controls were recruited by using random digit dialing in the same general population from which the cases arose, and data were gathered by in-person interview. No proxy interviews were conducted. Recall of oral contraceptive use may be less accurate than that of menopausal hormone use because oral contraceptives typically were used in the more distant past. However, controls and cases were matched on age to minimize differential bias due to misclassification. In addition, cue cards with photographs of the hormones and their packaging, along with hormone brand and generic names, were used to assist in recall of specific hormones. Rapid case ascertainment was used to identify cases shortly after diagnosis to minimize loss of cases because of death. However, women with follicular lymphoma and other more aggressive NHL subtypes may have been underrepresented in this study because these women were less likely to be interviewed because they were more likely to have died after diagnosis. Only incident validated cases were included in the study. This study does not directly address the possibility that nonestrogen hormones, such as progesterone and prolactin, might help to explain the observed associations, because few women used nonestrogen sex steroids for HT or other reasons. Interpretation of analyses by type of HT was limited by small sample size.

In summary, this large, population-based study shows that multiple pregnancies and, to some extent, use of HT and high-dose oral contraceptives, are associated with a reduced risk of NHL, particularly DLCL. These results support the hypothesis that exposures to estrogen and/or other reproductive hormones in women may induce favorable immunologic responses that reduce the risk of developing certain NHL subtypes and may help to explain sex differences in risk across subtypes. Further investigation is needed to confirm these results, to better characterize the heterogeneous NHL subtypes, and to better ascertain the underlying mechanisms of reproductive hormones in the pathogenesis of NHL. Large, pooled analyses through consortia such as the International Lymphoma Consortium (InterLymph) are warranted to increase the power to test hypotheses of the association between endogenous and exogenous hormone exposures and NHL and to investigate effects within rare NHL subtypes.


   ACKNOWLEDGMENTS
 
J. S. L. was supported by Grant Number UL1 RR024146 from the National Center for Research Resources (NCRR). Financial support was provided by grant CA45614 and in part by grants CA89745, and CA87014 from the National Cancer Institute, National Institutes of Health.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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