In this large cohort of female public school professionals, OC use was associated with a decreased risk of B-cell NHL among women who started OC use before age 25 years. However, the risk did not decline with increasing duration of OC use. We observed no overall association between either ET or EPT and risk of B-cell NHL. We observed a consistently, albeit statistically non-significant elevated risk for FL with all MHT use exposure measures. The risk of B-cell NHL increased by three-fold for women whose menopause was due to bilateral oophorectomy plus hysterectomy and who had never used any MHT; however, no increased risk was observed among women who had ever used ET only or EPT. Among women with a bilateral oophorectomy plus hysterectomy, ET use was associated with a 60% reduced risk. Neither ET nor EPT use was associated with B-cell NHL risk among women with natural menopause.
Our results for the association between OC use and overall B-cell NHL risk are consistent with some, 7,9,17,19 but not all studies.12,15 The only study that examined age at first use of OCs also reported a decreased risk for younger age of OCs initiation.19
Two studies examined OC use in relation to risk of NHL subtypes; in agreement with our study, no statistically significant association was observed for any subtype.19,20
Consistent with previous studies,9,10,15,19,20
age at menopause was not associated with B-cell NHL risk in our study. However, no prior studies have separated women with bilateral oophorectomy as the cause of menopause from those who had hysterectomy without bilateral oophorectomy prior to menopause. We consider this an important distinction, as the former group of women has no circulating hormones of ovarian origin after the surgery, whereas the latter group of women has at least some ovarian production of hormones after hysterectomy. Results from our study, although based on small numbers of cases, suggest that bilateral oophorectomy plus hysterectomy may be a strong risk factor for NHL among women who never used MHT, and that estrogen supplementation with ET may counter this increased risk.
The association between MHT use and NHL risk has been less consistent in prior studies. The substantial changes in the formulations of available MHT and patterns of use over the last several decades,21
together with the differences in distributions of types of menopause in different studies may account, in part, for the observed inconsistencies in risk estimates. In the Iowa Women's Health Study Cohort, MHT use increased NHL risk, particularly for nodal, follicular lymphoma.11
Our data are also suggestive of an increased risk of FL among MHT users.
Of studies on NHL and MHT use conducted to date, only the National Institutes of Health (NIH)–American Association of Retired People (AARP) Diet and Health Study Cohort provided information on MHT formulation (ET and EPT) and hysterectomy status,20
and few others could account for hysterectomy status or oophorectomy status.17
The NIH-AARP study, carried out contemporaneously with our study, reported null associations for women with an intact uterus who only used EPT and for women with hysterectomy who only used ET.20
In a comparable analysis, we assessed the association of ET use with B-cell NHL risk, restricting to women reporting a hysterectomy as the reason for cessation of menses, regardless of whether or not they had bilateral oophorectomy, and observed similar null results (RR=0.80, 95% CI=0.49-1.32) (data not shown). In our study, stratified analyses further demonstrated the null association between MHT use and NHL risk among women with natural menopause or those with hysterectomy defining last menstrual period.
One limitation of our study is the limited number of B-cell NHL cases available for some subgroup analyses such as those by menopausal status or by NHL subtype. Although we observed a decreased risk of B-cell NHL among women with bilateral oophorectomy plus hysterectomy who used ET-only formulations, this finding was based on a small number of NHL patients (n=68), only 10 of whom had not used any MHT. Another limitation of our study is that we considered MHT use up to a single point in time, the date of completion of the baseline survey, and did not consider changes in use or formulation after that time.
Major strengths of our study include its prospective design, an extensive evaluation of OC and MHT use duration and formulation, detailed information on hysterectomy and oophorectomy, comprehensive follow-up procedures, virtually complete ascertainment of cancer outcomes, and the use of the most current WHO Classification system for NHL subtypes.
In summary, we found a modest inverse association of OC use at younger age, and an overall null association of MHT use with B-cell NHL risk. Future research with larger sample sizes and detailed information on hysterectomy and oophorectomy status and MHT formulation will help clarify the role of ET among women with surgical-defined menopause and EPT among women with natural menopause in the development of NHL, and may lead to new insights into the etiology of this disease.