In this retrospective case control study we investigated the possible effect of hysterectomy on SLE disease onset and ACR criteria in our available lupus patients. We found that lupus patients with a history of hysterectomy before SLE onset, had milder disease with less nephritis, less anti-dsDNA and a later age of disease onset than did lupus patients with a negative history for this procedure. This effect was observed in both European-American and African-American subjects. Biologically, the protective effect of hysterectomy with oophorectomy which causes a surgical menopause, can be expected. To our knowledge, however, there are no recent reports that address this issue in SLE. In a study reported in 1985, Grimes et al. suggest the possible protective effect of prior hysterectomy or tubal sterilization on SLE because their SLE cases were less likely to have a hysterectomy than controls (OR= 0.54, 95% CI=0.29–0.99) (8
). However their sample sizes were small. Thus, once adjusted for age, the finding was not statistically significant 0.73 (95% CI= 0.40–1.50) and simultaneous adjustment for age and race was not performed. In our study, SLE patients were, indeed, more likely to have had hysterectomy both before and after SLE onset than age matched controls (). When comparing cholecystectomy or tonsillectomy before SLE onset, there were no significant differences between cases and controls.
In our data, the increased rate of hysterectomy also was observed among family members of lupus patients compared to normal controls and, interestingly, the highest trend was observed among subjects with intermediate lupus (i.e. those subjects that failed to meet the 4 criteria for SLE diagnosis) (). This further suggests that a hysterectomy may help to protect against full blown disease manifestations. Indeed in this group of intermediate lupus subjects with borderline criteria, those with past surgical history of hysterectomy, had either a negative ANA or low titer (≤120) at the time of participation in the study compared to those with a negative history (European-American 73% vs. 50%, OR=2.72, 95% CI=1.43–5.18, P=0.002); African-Americans 67% vs. 47% OR=2.36, 95% CI=1.03–5.38, P=0.03). Similar trends were observed among controls and other family members but the results were only suggestive (data not shown).
To our knowledge there is no report in humans to examine any possible effect of previous hysterectomy on ACR criteria or age of disease onset in lupus. Our data suggest that some ACR criteria, especially those related with more severe disease such as nephritis and the presence of anti-dsDNA antibodies, could be more influenced by previous hysterectomy than other criteria.
It has been known for decades that the strongest risk factor for SLE is female gender. It has been shown that the sex ratio at age of onset rises with puberty from 2:1 to almost 10:1 in young adulthood and declines with female menopause in the sixth decades (9
). Studies performed in (NZBxNZW) F1 hybrid mouse, a murine model of SLE, also support the role of female hormones in the modulation of the autoantibody titer and development of renal disease and death (10
). However, the relationships between the reproductive factors and sex hormones are complex and it is difficult to explain the pathogenesis of SLE by hormone factors. Other effects, such as X chromosome gene dose effect or susceptibility genes acting in one sex or the other also contributed (11
It is important to mention that hysterectomy by itself could affect the ovarian function and could result in early menopause and premature ovarian failure in some cases (13
). Therefore, even hysterectomy without ovariectomy may be potentially important in SLE. Although the rate of concomitant ovariectomies that more importantly affect the female hormone balance were not available in all of our cases, however in limited available data in medical records, from 155 cases with history of hysterectomy before SLE onset, 81 European cases have been identified with concomitant history of unilateral or bilateral oophorectomy and strikingly none of them had any evidence of kidney nephritis. Similar trend were observed in African-American cases as described previously however the number of cases were limited and further studies are needed to confirm these preliminary findings. Furthermore, endometrial and ovarian autoantibodies have also been reported to be commonly seen in female SLE patients than healthy controls, although significance of these autoantibodies are not clear (14
Based on separate query from the general questionnaire on whether or not the subjects take hormones, more than 90% of our patients who had undergone hysterectomy were on hormone replacement therapies (HRT) at the time of participation to the study. However this query didn’t address the dosage, duration of therapy or combination of hormones used. Usually patients who have undergone a hysterectomy are given estrogen therapy alone while a progestin is added to estrogen in postmenopausal women with a uterus, in order to prevent endometrial hyperplasia or cancer (15
). The decision for using long-term HRT depends on many factors such as age, health status and cardiovascular disease risk factors. On average, only 20% of HRT users are maintained treatment for at least 5 years or more (15
). In our data, conditional analyses based on hormone therapy, didn’t affect the results in ACR criteria and in group of patients with negative history for hysterectomy there was no significant difference in ACR criteria based on this query.
Based on our available medical records we could not find any significant difference of the underlying causes of hysterectomy between cases and controls and uterine fibroids or uterine bleeding were common in both groups as expected. Without a doubt underlying female hormonal balance plays a key role in leading to conditions such as persistent uterine bleeding or fibroids that ultimately need surgical treatment. This balance is under control of genetic factors as well as environmental elements such as diet and xenoestrogen consumptions, or a combination of both. We speculate that SLE patients may be more likely to have irregularities in hormonal balances (e.g a dominant estrogen state) and are, therefore, more likely to have a hysterectomy due to the complications of these irregularities. These patients would sooner reach early menopausal states with less severe disease manifestations. The similar observed trend in SLE family members can be explained by shared genetic and environmental elements. Further studies are needed to confirm or refute this possibility.
Currently, our understanding of the link between environmental risk factors and rheumatic diseases such as SLE is very limited. In conjunction with whole-genome scans that have changed dramatically our understanding of complex diseases such as SLE, the whole-environmental scans could change dramatically the capacity to define gene-environmental risk factors in the future. This can only be possible by integrating an extensive exposure questionnaire into a genetics database.