The present results are the first prospective data on risk factors for uterine leiomyomata in Black women. The Nurses’ Health Study II published prospective data on uterine leiomyomata (17
), but their case group comprised only 5 percent Black women, and the results on reproductive factors were not stratified by race. The rate ratios observed in the present study are consistent with those found in studies of White women. Risk was inversely associated with age at menarche, parity, age at first birth, and current use of injectables and positively associated with years since last birth. While age at first oral contraceptive use was weakly inversely associated with risk, null associations were found for duration and recency of use, hormonal potency, classification of progestin, and formulation of oral contraceptive.
Epidemiologic studies on age at menarche in relation to uterine leiomyomata have shown an inverse association (13
). The inverse association found in the Black Women’s Health Study and other studies supports the hypothesis that women with an early age at menarche have, on average, increased menstrual cycling and greater lifelong exposure to bioavailable estrogens, which are thought to promote growth of uterine leiomyomata. Early age at menarche has been correlated with higher levels of estradiol (38
) and estrone and lower levels of sex hormone binding globulin (39
The decreased risk of leiomyomata in parous compared with nulliparous women is consistent with results from previous research (12
), although our study did not confirm the dose-response reduction in risk for parity that has been shown in some (12
), but not all (17
), studies. The lack of an association for spontaneous or induced abortion agrees with findings from other studies (12
) and suggests that the protection conferred by pregnancy may relate to full-term pregnancy only. Inverse associations for parity remained after the exclusion of women reporting a history of infertility and after accounting for lifetime lactation. Although lactation is thought to suppress ovarian hormones (37
), our study does not support an association with leiomyomata, in accord with the two other studies that have examined lactation (18
). Excess body weight appeared to weaken the inverse association observed for parity, as women with a body mass index above the median had only half the parity-related reduction in risk of women below the median.
Hormonal and nonhormonal mechanisms may explain the inverse association with parity. First, higher parity reflects a decrease in menstrual cycling. Second, a full-term pregnancy induces significant long-term changes in levels of ovarian hormones and growth factors (42
), including lower levels of plasma and urinary estradiol (38
), higher levels of sex hormone binding globulin (44
), and long-term decreases in basal levels of prolactin (46
). Third, full-term pregnancy may cause a reduction in estrogen receptor levels in myometrial tissue, which could reduce the sensitivity of leiomyomata to hormonal stimuli (48
). Fourth, extensive uterine tissue degradation and remodeling occurs both during and after full-term pregnancy (49
). Collagenases and other tissue-degrading enzymes induce apoptosis and may inhibit the growth of preneoplastic or neoplastic cells (49
In line with other studies (12
), the risk of uterine leiomyomata in the Black Women’s Health Study increased with increasing time since last birth. The time-risk relation between parity and risk of leiomyomata is similar for uterine cancer (50
), which supports the hypothesis that the protection conferred by parity may be related to pregnancy-related hormonal changes or the mechanical shedding of transformed myometrial cells. A recent NIEHS study demonstrated that a first birth occurring in the mid-reproductive years (ages 25–29 years) was most protective against leiomyomata, while births at other ages showed no association with risk (37
). Our study did not replicate these findings but, rather, showed an inverse linear relation with age at first birth, regardless of whether analyses included primiparous or all parous women.
There was no clear association between oral contraceptives and risk of uterine leiomyomata in the Black Women’s Health Study. While two studies found that ever users of oral contraceptives were at reduced risk (14
), others found little or no association (12
) or increased risk (21
). Only one study found a reduction in risk as the number of years of oral contraceptive use increased (14
). Our finding of an increased risk associated with early age at first oral contraceptive use is consistent with that of one other study (17
). In contrast to a study that found a reduction in risk associated with increasing dose of progestin (14
), we found no association with progestational potency or progestin classification. Although the validity and clinical relevance of potency information have been questioned (51
), we carried out these analyses because other diseases, such as breast cancer (52
), ovarian cancer (53
), and vulvar vestibulitis (54
), have been linked to oral contraceptive potency.
Current use of progestin-only injectables was associated with a decreased risk of uterine leiomyomata relative to nonuse of hormonal contraception. A Thai study showed a similar inverse relation between the use of DMPA, an injectable progestin, and surgically confirmed leiomyomata (18
). In that study, the reduction in risk was most pronounced for women using DMPA for 5 or more years and for current users. In the Black Women’s Health Study, the inverse association for use of progestin-only injectables remained unchanged after excluding past users. This suggests that the inverse association was not influenced by the inclusion of women with subclinical leiomyomata who may have discontinued DMPA because of irregular bleeding.
Use of DMPA has been associated with an increase in gonadotropin-releasing hormone pulse frequency, modification of the endometrial lining, suppression of gonadotropins, and reduced secretion of estradiol (55
) and progesterone. Progestins may also downregulate the estrogen receptor in leiomyomata (57
). Estradiol concentrations in DMPA users resemble postmenopausal levels, and the degree of estradiol suppression may increase with longer use (55
). Findings for progestin-only oral contraceptives and implants were uninformative because of small numbers.
In the Black Women’s Health Study, information on reproductive and contraceptive histories was collected before the diagnosis and confirmation of leiomyomata. This prospective design eliminates the potential for recall bias because cases reported their exposures prior to their diagnosis of leiomyomata. Although it is still possible that leiomyomata developed years before their clinical diagnosis, it is unlikely that women would have modified their lifestyle without the experience of symptoms or the clinical diagnosis of the condition.
We validated self-reported uterine leiomyomata through a detailed supplementary questionnaire and review of medical records. We were able to confirm the diagnosis in 96 percent of the cases for whom we obtained medical records. We cannot rule out the possibility that women who released their records reported with greater accuracy than those who did not. Results based on the most secure case definition, hysterectomy-confirmed leiomyomata, were similar to those based on the larger group that included ultrasound-confirmed cases. The one exception was that parity was not inversely associated with risk in the hysterectomy group. Differences between ultrasound- and hysterectomy-confirmed cases may be related to factors associated with patient or physician preference regarding the choice of treatment rather than the true incidence of leiomyomata (23
). For example, if cases who had completed childbearing were more likely to choose hysterectomy as a form of contraception than cases who had not finished childbearing, then our association for parity would have been upwardly biased.
As in most other large-scale epidemiologic studies (7
), Black Women’s Health Study participants were not systematically screened for uterine leiomyomata. Because of the high incidence of these tumors and their tendency to be asymptomatic, some cases were undoubtedly misclassified as noncases. In a recent NIEHS study that screened randomly selected women aged 35–49 years from an urban health plan, 59 percent of premenopausal Black women who had not reported a previous diagnosis of leiomyomata showed ultrasound evidence of the condition (9
). The degree of misclassification increased with age (9
). In the Black Women’s Health Study, if misclassification was unrelated to any of the reproductive factors examined, the observed incidence rate ratios would have been biased toward the null. However, among women aged less than 35 years, a “low-risk” group in which misclassified cases would have constituted a smaller proportion of true noncases, findings were similar to those for the entire study group.
If any reproductive factor influenced the detection of leiomyomata, over- or underestimation of the incidence rate ratio could have occurred. For example, women who visited a physician for any factor that increased their likelihood of pelvic examination (e.g., prenatal care) would have been more likely to have an incidental diagnosis of leiomyomata, which would have upwardly biased the incidence rate ratio for parity. Given that parity was inversely associated with leiomyomata in the Black Women’s Health Study, we would expect the true association to be even stronger than what we observed. Likewise, the observed incidence rate ratios for oral contraceptive use may have been inflated because of detection bias. Data from our validation study show that a high proportion of cases (70 percent) had symptoms prior to the detection of uterine leiomyomata and that 55 percent of cases sought medical care for symptoms prior to detection of the condition. While this leaves room for detection bias, restriction of the sample to women reporting a Papanicolaou smear within the previous 2 years did not appreciably change our results, suggesting that detection bias played a minor role.
Findings generated from a follow-up study can be compromised if response is low within each cycle of follow-up and there is permanent loss to follow-up. The Black Women’s Health Study response of over 80 percent reduces the potential for selection bias. Length of follow-up did not differ significantly by parity, oral contraceptive use, body mass index, or age at menarche, but significant differences were noted for education. In a comparison of women with less than 12 years versus 17 or more years of education, the mean length of follow-up was 37.1 months and 39.8 months (p
< 0.001). When we used Robins’ method of inverse probability of censoring weighting (58
) to account for differential loss to follow-up—a method that weights women who were not lost to follow-up more heavily to account for women who were, given the same covariate history—our results did not change materially.
Black Women’s Health Study participants may differ from the general population of US Black women in ways that may affect the generalizability of our findings. However, the median ages at menarche, age at first birth, and body mass index in the cohort were similar to those documented in nationwide representative studies of Black women (59
). Moreover, we did not find any effect modification by education, smoking, or alcohol consumption on the main associations of interest. Therefore, the present findings are likely to extend to other US Black women.
Reproductive history is an important determinant of uterine leiomyomata in US Black women. Several national studies show that Black girls have an earlier mean age at menarche than White girls (59
) and that Black women are more likely to begin and end childbearing at earlier ages (61
). However, evidence from studies including Black women and White women, combined with the modest associations found in the Black Women’s Health Study, suggests that reproductive factors explain only a small fraction of the Black-White difference in rates of uterine leiomyomata (16