Generally, we observed the same associations between age at menarche, parity, age at first birth and time since last birth and UL as Marshall and colleagues (8
), although we were able to evaluate finer categories due to our extended follow-up.
The inverse association in our data between age at menarche and UL risk is consistent with previous studies (7
), although sometimes the association in previous studies did not reach significance (13
). To our knowledge observations between current cycle pattern and UL risk have not been previously reported. We observed that women with the longest cycle lengths or always irregular pattern were less likely to develop UL, perhaps due to less exposure to ovarian steroids. Conversely, women with extrememly regular cycles, who are unlikely to have anovulatory cycles, may have a reduction in risk due to regular progesterone exposure.
Consistent with earlier reports, parity was inversely associated with UL risk (8
). Previously, the inverse association between parity and UL had been questioned since nulliparous women could be infertile (9
). However, we observed an inverse association between parity and UL in both fertile and women who reported problems with fertility suggesting that parity is independently associated with UL.
We observed a trend in decreasing UL risk with longer duration of breastfeeding that was apparent across categories in the age-adjusted analysis but only evident after 19 months in the multivariate adjusted model. Investigators from the Black Women’s Health Study also evaluated the association between breastfeeding and UL risk and observed no association across categories ranging from <1 month to ≥ 24 months (14
). Although these data appear to be at odds, the confidence intervals overlap, and we have greater power to detect an association at the highest categories where the association is evident.
Though there are many potential influences on UL development [reviewed in (4
)], endogenous hormones are hypothesized to be instrumental. UL incidence increases until menopause and GnRH agonists, which shut down gonadal hormone production, are an effective UL treatment (4
). In addition, UL symptoms are often relieved with menopause but some women report that symptoms continue or develop with hormonal replacement therapy. Thus, our observations may be explained by extended exposure to endogenous estrogen and progesterone. For instance, decreasing risk with increasing age at menarche may be a reflection of decreased lifetime exposure to gonadal hormones. Similarly, breastfeeding, which induces amenorrhea and therefore periods of decreased estrogen/progesterone exposure, also reduced UL risk.
Though both estrogen and progesterone are elevated during pregnancy, progesterone, the predominant hormone, is required to establish and maintain the pregnancy (17
) and may reduce UL risk. Baird and Dunson proposed that pregnancy is protective due to remodeling during uterine involution in the weeks following delivery (18
). Alternatively, UL may develop in response to damage to myometrial cells during menstruation (19
). Our observations regarding pregnancy, lactation, late age at menarche, and long menstrual cycle length would support this theory since all these exposures involve fewer menstrual cycles.
Our study is limited by the fact that many UL are asymptomatic and UL are identified in our study by self-report. Therefore, the UL identified by our study participants are likely to be symptomatic. Baird and colleagues have shown that 50% of women aged 35–49 with no previous history of UL will have a UL detected by ultrasound (18
). Consequently, spurious associations may be observed between exposures that are associated with medical surveillance and UL. For instance, women receiving prenatal care may be more likely to have a UL detected. However, this would increase UL diagnoses among pregnant women and lead to a spurious positive association between parity and UL. Since we observed a decreased risk of UL with increasing number of pregnancies this type of bias is unlikely, although the true association could have been attenuated by an excess of UL diagnoses among pregnant women.
In addition, differences in multivariate and age-adjusted estimates suggest a role for confounding in these associations. Although we have adjusted for known and suspected UL risk factors, residual confounding could still account for some observed associations. Given the large number of statistical tests performed in this analysis, some associations could be statistically significant by chance. However, all of the exposures evaluated were selected a priori, minimizing the likelihood of a chance finding.
With respect to public health significance, UL that come to clinical attention are the most relevant to study and understand since these are a source of considerable morbidity. Undetected UL are more likely to be asymptomatic (20
); therefore, identification of factors involved in the initiation of UL development may not be as clinically important.
In our study, the proportion of new UL (9%) and new and existing UL combined (14%) is lower than the UL prevalence reported in other studies (21
), likely due to the overwhelmingly Caucasian composition of our study population. Since UL are more common in African American women (15
), the generalizability of our results are limited.
Our prospective analyses among premenopausal U.S. registered nurses suggest that late age at menarche, long menstrual cycles, parity, late age at first and last birth, short time since last birth, and breastfeeding reduce UL risk. The large sample size, prospective design, detailed assessment of menstrual and reproductive characteristics, and updated exposure and covariate information of the Nurses Health Study II allowed us to add to the limited knowledge of menstrual and reproductive characteristics and UL risk.