The nine studies from parts of North America, Europe and Japan suggested that postmenopausal women who used hormone therapy had a lower risk of NHL overall than those who had never used it. Current users were at decreased risk, but past users had risks comparable to those who had never taken hormonal therapy. Risks below one were found in all categories of duration of use and age when hormonal treatment started; no clear trends were found for either variable. Findings were similar when these analyses were restricted to current users. When hormones were started between the ages of 50–54, the decreased risk reached statistical significance. For the two most common subtypes, DLBCL and FL, findings were similar to NHL overall. Findings were consistent among population-, hospital- and clinic-based studies, in studies where case and control participation was over 70%, and when risk estimates were adjusted for socioeconomic status.
Other evidence for postmenopausal hormone therapy's role in NHL aetiology comes from five cohort [5
] and two case–control studies [6
]. Among these further studies, one case–control study reported that hormonal therapy reduced the risk of NHL overall [6
] but on the whole, cohort studies found risks to be around one. For DLBCL, two cohorts reported risks below one [5
] while two others found no association [7
]. As for FL, there has been less consistency, with one study reporting a risk below one [11
], another close to one [5
] and two raised [7
], one of which was statistically important [14
]. When we conducted a meta-analysis of cohort data, the results suggested no association with ever use for NHL, DLBCL or FL (pooled risk estimate = 1.01, 95% CI 0.89–1.14, I2
= 0%, Pheterogeneity
= 0.49; pooled risk estimate = 0.87, 95% CI 0.67–1.14, I2
= 21%, Pheterogeneity
= 0.28; pooled risk estimate = 1.31, 95% CI 0.70–2.45, I2
= 76%, Pheterogeneity
= 0.01, respectively). However, our protective finding was among women who were using hormonal therapy 1 year before diagnosis. Current users were also at reduced risks in one cohort [5
] and a case–control study [6
], but not two other cohort studies [7
] (Figure ). Cohort studies would have collected information on hormonal therapy many years before diagnosis. Interestingly, studies with follow-up periods that were shorter and closer to menopausal age found risks for current users more similar to ours while for longer follow-up and further from menopause, risks were closer to one (Figure ). One cohort reported a lower risk after 7 [24
] than after 13 years of follow-up [14
]. In cohort studies, information may not have been available as to whether women had stopped using hormone therapy since recruitment into the cohort. One possible explanation for differences between our study and the cohorts' findings is that in cohorts, women may have been more likely to have stopped where follow-up continued further from menopausal age.
Figure 1 Associations between non-Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma and current use of postmenopausal hormonal therapy reported in published studies. Current use of hormone therapy was reported at recruitment in cohort studies (more ...)
In our data, whether oestrogen only or combined oestrogen and progestin therapy contributed to the reduced risk could not be examined directly as only one study collected this information. As an alternative, we investigated whether risks were different among women who had or not had a hysterectomy since from the late 1980s, unopposed oestrogen tended to be prescribed following a hysterectomy and combined therapy to menopausal women with an intact uterus [4
]. Although we found no difference for NHL overall, decreased risks of DLBCL for hormonal therapy were found among women who had had a hysterectomy in particular, but also in those who had not. For FL, risks were reduced among women with an intact uterus and not among those who did not. Findings for the two formulations have been reported in two cohorts [5
] and one case–control study included here [10
]. No associations with either therapy were found in the cohort studies [5
] while reduced risks were found for both therapies in the case–control study [10
]. However, some decreased risks were found in the cohort studies when hysterectomy data were considered in conjunction with treatment types [5
]. In the NIH-AARP cohort, women who had had a hysterectomy and were treated with unopposed oestrogen were at decreased risk of DLBCL while women with an intact uterus and on oestrogen plus progestin were not [5
]. The California Teachers Study found that removal of both ovaries increased the risk of B-cell NHL possibly due to the absence of circulating hormones of ovarian origin, and when oestrogen only therapy was given to ovariectomized women, the treatment mediated the increased risk [7
]. Hence, there appears to be some consistency between these findings [5
] and ours, but further investigation on treatment type is needed.
The mechanisms by which hormone therapy may act to reduce NHL risk among postmenopausal women are not known but may involve pro-inflammatory cytokines such as interleukins and tumour necrosis factor. As age increases, changes in immune function occur [3
]. These alterations, which include increased production of pro-inflammatory cytokines, may be increased further in postmenopausal women due to oestrogen deprivation, at least in the years soon after menopause [25
]. Taking hormone therapy may normalize the immune response and decrease production of tumour necrosis factor and interleukin-6 [2
]. Such mechanisms may explain the lower NHL risk in postmenopausal women who take hormone therapy compared with those who are untreated, although the exact processes by which hormone therapy acts on the immune system and lymphomagenesis are unknown. We also found a reduced risk of DLBCL among hormone therapy users of normal weight, a finding that has not been reported before. Although adipose tissue is a major source of oestrogen in the postmenopausal period, being overweight may increase DLBCL risk [26
] and so other obesity-related alterations to immune function are likely to be involved.
Our studies, like others of similar design, have several limitations. First, the use of postmenopausal hormone therapy was self-reported, although evidence suggests that there is reasonable agreement with medical records [8
]. Secondly, the controls' hormone therapy use may not be typical of postmenopausal women in general. Data for comparison are lacking, but across case–control studies, it seems unlikely that there is systematic selection bias given that hormone therapy has also been associated with disease excess, most notably breast cancer [32
]. Thirdly, we could not assess risks associated with the type of postmenopausal hormone therapy, route of administration and dose as most studies did not collect this information. Fourthly, our finding of a decreased risk with current use could be a consequence of cases stopping use as lymphoma ensues. However, 75% of cases who were using hormone therapy at 1 year before diagnosis were still using it at the time their lymphoma was diagnosed. Fifthly, some cases would have died soon after diagnosis or been too ill to be interviewed, while a minority of interviewed cases may have had another cancer before their NHL diagnosis. Whether these cases were more (or less) likely to have used hormone therapy than those who were interviewed or who did not have a previous cancer is uncertain. Sixthly, it is also not known whether cases were less likely than controls to have had menopausal symptoms or conditions such as osteoporosis which are treated with hormone therapy. Lastly, our findings may be a consequence of selection bias since our controls tended to be of higher socioeconomic status than cases. Women of higher socioeconomic status are more likely to take hormones to treat menopausal symptoms than those of lower, but nevertheless, our protective effect remained when risks were adjusted for socioeconomic status.
In this pooled analysis of individual data, we found protective associations between postmenopausal hormone therapy and NHL and its two most common subtypes, DLBCL and FL. Our findings suggest that current use may reduce NHL risk. An advantage of our data, as well as the large number of subjects, was the ability to study hormone therapy use up to the time of diagnosis. The implications of our findings are not the prevention of NHL by taking postmenopausal hormone therapy since its use can lead to the development of breast and endometrial cancers and cardiovascular disease. Rather, our study gives insight into the possible role of exogenous sex hormones on NHL aetiology.