1 Department of Epidemiology, Institute of Social Medicine, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
2 Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD.
3 Department of Gynecology and Obstetrics, School of Medicine, Johns Hopkins University, Baltimore, MD.
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ABSTRACT |
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blacks; case-control studies; hormones; leiomyoma; reproductive history; risk factors; uterine diseases; women
Abbreviations: CI, confidence interval; OR, odds ratio; UL, uterine leiomyoma.
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INTRODUCTION |
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For many years, there has been a medical notion based on uncontrolled observations that African-American women have a higher incidence of UL than White women (3, 4
). In recent years, US registration data from hospital discharge and hysterectomy records have tended to confirm this association (1
, 2
, 5
). In addition, a 3.3-fold increased risk of UL was observed prospectively among African Americans in Nurses' Health Study II (6
). In contrast, self-reported UL was less prevalent in African Americans than in Whites among controls initially selected for the Cancer and Steroid Hormone Study (7
).
Other than ethnicity, several characteristics have consistently been found to be inversely associated with UL in the few published studies on the topic: parity (711
), age at first or last childbirth (8
11
), age at menarche (7
, 9
, 11
, 12
), and menopause (7
, 8
, 10
, 12
). Conflicting data have emerged regarding the roles of oral contraceptives (7
9
, 11
, 13
), smoking history (7
, 8
, 14
16
), and obesity (7
, 8
, 12
, 14
, 16
). Some of the heterogeneity in the findings may be due to the diversity of case definitions, which can include less specific diagnostic entities (16
), self-reported UL (7
), more severe surgical cases (8
, 12
), and sonographically or surgically confirmed cases (11
, 14
). UL is very common, is predominantly asymptomatic, and frequently has a mild clinical course; in addition, medical handling of these cases may vary from clinical or ultrasonographic follow-up of tumors to hysterectomy (17
). Because most previous studies have been based on surgical cases, some results may have been vulnerable to selection bias and temporal bias.
Until recent years, the prevailing causal theory regarding UL was that estrogenic stimulation of the myometrium, unopposed by progesterone, was the main determinant of UL development, or at least of its growth (710
). This hypothesis was originally formulated to explain findings from epidemiologic studies on the etiology of endometrial cancer (18
). However, accumulating clinical, biologic, and epidemiologic evidence suggests that both estrogen and progesterone are important in the development of UL (11
, 19
).
This report presents findings from Baltimore, Maryland, on relations between UL and selected characteristics associated with endogenous and exogenous hormonal exposures and self-described African-American ethnicity. In a companion paper (20), we report exploratory findings regarding the possible etiologic role of atherogenic and local irritational factors.
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MATERIALS AND METHODS |
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Study participants were residents of the Baltimore Standard Metropolitan Statistical Area, which comprises Baltimore, Harford, Howard, Queen Anne's, Carroll, and Anne Arundel counties. In order to focus on a population most likely to develop UL, we excluded postmenopausal patients. Patients were considered to be postmenopausal if the date of the last menstrual period, as reported in medical records, was more than 6 months before the date of the index visit and if the records did not mention any situations or conditions that induce suppression of menses.
Cases were first diagnosed with UL (International Classification of Diseases, Ninth Revision, code 218) by collaborating gynecologists on the basis of symptoms or abnormal pelvic examination findings between January 1, 1990 and June 30, 1993. This case definition included asymptomatic UL diagnosed during a routine pelvic examination; however, it excluded tumors that had not been suspected prior to the confirmatory diagnosis, such as those detected incidentally during hysterectomy or during uterine ultrasound that was indicated for the diagnosis or treatment of another gynecologic condition.
Our case series can be viewed as representing the treatment situation of an open cohort of newly diagnosed cases during 3.5 years of follow-up. Therefore, both nonsurgical and surgical (hysterectomy and myomectomy) cases were included.
Diagnoses had to have been confirmed by histologic findings (surgical cases) or by at least one uterine sonogram; nonsurgical cases were excluded if sonogram reports included any phrases such as "questionable UL" or "possible UL" (57 cases). Two cases with atypical histologic features suggesting borderline malignant cell behavior were excluded. Additionally excluded were 34 case women with a history of gynecologic or breast cancer and three disabled case women (one deaf and two with mental retardation).
Controls were patients with intact uteri who had visited the same physicians for a routine checkup that included a pelvic examination, without mention of physical findings consistent with UL. In addition, these patients' medical records had to have no mention of confirmed or suspected UL. Other inclusion criteria pertaining to cases were also applied to controls: residence in the Baltimore area, premenopausal status, no history of invasive gynecologic or breast cancer, and an absence of conditions interfering with a successful telephone interview. No controls developed clinically detectable UL during the study period.
Ascertainment of participants, data collection, and analysis
To identify potential participants, trained personnel screened all available medical charts, and they identified 1,294 patients as having a diagnosis of UL; among these, 409 eligible cases (31.6 percent) were identified. To select controls, study personnel searched lists of patients ordered by date of visit for the same 6-month periods as those of the cases' diagnostic confirmation dates. A total of 1,389 charts were screened, and 505 eligible controls (36.4 percent) were identified.
After reviewing the information on potential cases and controls, we made final decisions on which participants to include as eligible for contact. Disagreement between us and the abstractors occurred in relation to 16 and 24 patients initially judged to be eligible as cases and controls, respectively. In addition, we reviewed a systematic sample (20 percent) of charts from those patients considered ineligible by each abstractor.
Controls were frequency-matched to cases within strata defined by 10-year age group, 6-month calendar period (JanuaryJune or JulyDecember) of the index medical visit, and collaborating gynecologist. For cases, the index medical visit was defined as the visit prior to the date of diagnostic confirmation of UL; for controls, the index visit was defined as the first routine visit (following a randomly selected starting day) during the same 6-month period.
A personal contact letter supporting the study and encouraging participation was sent to all eligible participants by their gynecologists. Telephone interviews followed a structured questionnaire and were conducted between February and October of 1994 by five female college graduates who had attended a 40-hour training program. A total of 318 cases (77.8 percent of the total eligible) and 394 controls (78.0 percent of those eligible) were successfully interviewed. No surrogate respondents were interviewed. The proportions of eligible cases and controls who participated were similar across clinics.
The interviewers' part of all answered calls and interviews was tape-recorded; a trained supervisor listened to every fifth tape returned by each interviewer. Quality problems, when detected, were discussed with interviewers on a weekly basis.
The study was introduced to interviewers and respondents as the "Baltimore Women's Health Study," a survey on frequent gynecologic conditions. Interviewers were not told of the case or control status of participants, and they interviewed controls and cases in similar ratios. The mean duration of the interview was 14.2 minutes (standard deviation 4.5). Most participants' (98.2 percent) cooperation was rated by the interviewers as either "very good" or "good"
Cases and controls were asked to provide information on sociodemographic characteristics (date of birth, marital status, years of education, racial/ethnic background); medical history of hypertension and diabetes mellitus; age at menarche; usual menstrual patterns when participants were in their "late teens and twenties"; reproductive history; history of infertility (defined as an unsuccessful attempt to get pregnant for 1 year or more or having ever sought professional help for infertility); use of oral contraceptives and intrauterine devices; perineal use of talc; history of pelvic inflammatory disease; family history of hysterectomy due to UL; smoking history; height; body weight at three time points (at interview, 5 years before interview, and at age 18 years); and usual frequency of dental checkups. We calculated body mass index as current weight (kg) divided by height squared (m2).
No later than 2 weeks after the interview, abstraction of medical records was carried out, with the exception of the 23 interviewees who refused access to their records (3.9 percent and 1.4 percent of interviewed cases and controls, respectively). Abstractors were not told of the study-specific hypotheses, and they abstracted controls' and cases' charts in a similar ratio. The first author (E. F.) conducted an independent abstraction of a systematic sample (20 percent) of medical records; in this sample, 1.7 percent of the abstract forms were found to include inaccurate data.
Characteristics abstracted from medical charts included: age at menarche; date of first visit to the study physician and number of visits to the physician during the past 3 years; and history of abnormal Papanicolaou smears, pelvic inflammatory disease, sexually transmitted diseases, benign breast disease, endometriosis, and endometrial hyperplasia. Additional data abstracted from cases' charts were: presence of symptoms typical of UL and abnormal findings upon pelvic examination prior to diagnostic confirmation; nonsurgical or surgical (hysterectomy or myomectomy) management of UL; number of diagnostic sonograms; presence of additional diagnostic reports; number of tumors; and size and location of the three largest tumors. Abstraction of charts was conducted by the research assistants who had previously identified eligible participants.
Continuous variables were categorized according to a priori rules: tertiles of exposure in the total study population, when a clear-cut exposed group existed (e.g., nonsmoking vs. tertiles of smoking duration); quartiles of the total study population, when the concept of a discrete exposed group did not clearly apply (e.g., quartiles of body mass index); and life decades or half decades for age-related variables, to achieve categories of size as similar as possible.
Analyses excluded events and exposures occurring after the date of the index medical visit, such as pregnancy and episodes of pelvic inflammatory disease; diagnoses of hypertension, diabetes, and infertility; and use of oral contraceptives, intrauterine devices, and talc. Analyses of age at menarche were based on information given during the telephone interview. The few participants who described themselves as belonging to "other" ethnic groups were pooled with Whites, because the two groups had odds ratios that were almost identical.
After conducting an initial assessment of confounding and effect modification in stratified analyses that included all relevant study variables, we used unconditional logistic regression models fitted by the method of maximum likelihood (21) to simultaneously adjust for confounding. For each study exposure, we fitted a first model with age and clinic, used for frequency-matching of the study groups. We built a second model with all potential confounders included, and this was followed by sequential cycles of variable deletion utilizing the "change-in-estimate" approach (22
): Among variables in a given model, a variable was selected for deletion if its deletion resulted in a change in the odds ratio of less than 10 percent. In the text below, we focus on the fully adjusted estimates obtained from the second model; however, for informational purposes, the tables also show results obtained from the first models. We conducted trend tests, when appropriate, by assigning the midpoints of the categories as data points and treating the scored variables as continuous.
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RESULTS |
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On average, cases and controls had similar histories of nulliparity and number of full term pregnancies (table 3). Cases were younger than controls, on average, at both first and last childbirth. An inverted J-shaped relation was suggested between age at first or last birth and the adjusted odds of UL, with nulliparous women taken as the reference category. First birth before age 25 years and last birth before age 30 years were positively, albeit not significantly, associated with UL. In contrast, odds ratios below 1.0 were observed in the older categories of age at first or last birth.
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Additional analyses focused on the associations of UL with age at first birth and age at first being found infertile according to UL location within the uterus (table 4). For the purpose of these analyses, UL location was categorized in terms of the presence (40 cases) or absence (71 cases) of submucous tumors, when such information was available from medical records. The adjusted estimates, although imprecise, suggest the existence of positive associations of UL with parity when submucous tumors are absent and negative associations when such tumors are present. Furthermore, these data suggest that while infertility is not associated with UL when submucous tumors are absent, there is a positive association when they are present, and that the association is especially strong (OR = 7.2; 95 percent CI: 2.0, 26.0) when participants are first found to be infertile before age 25 years.
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No statistically significant associations were observed between cigarette smoking variables and UL risk (table 5). Cases and controls were similar regarding lifetime pack-years of smoking. However, cases reported a slightly longer duration of smoking than controls, and some suggestion emerged of an inverse linear trend across categories of smoking duration; those who reported smoking for 19 years or more had a 40 percent decreased UL risk vis-à-vis never smokers (OR = 0.6; 95 percent CI: 0.4, 1.1).
To indirectly evaluate the likelihood of detection bias, we repeated the analyses after excluding participants with less than one gynecologic visit per year and less than one dental visit per year (as an indicator of general health behavior). In relation to menstrual and pregnancy history, oral contraceptive use, body mass index, and smoking history, these exclusions did not have an important impact on the study estimates. In contrast, when both variables (frequency of gynecologic and dental visits) were included in the model, the strength of the association between UL and African-American ethnicity increased, as reflected by the increase in the adjusted odds ratio from 9.4 (table 2) to 16.0.
Analyses were also conducted after exclusion of cases who had no typical symptoms prior to diagnosis. In addition, we refitted logistic regression models after excluding cases whose diagnostic confirmation had been based on a single uterine sonogram. Estimates were virtually un-changed in both situations.
Finally, we studied the agreement between age at menarche reported at interview and age at menarche recorded from medical charts; the weighted kappa coefficients, based on the categories of age at menarche used in the analysis, were 0.83 (95 percent CI: 0.77, 0.88) for cases and 0.82 (95 percent CI: 0.76, 0.88) for controls.
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DISCUSSION |
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Interpretation of the greater occurrence of UL among African-American women has been limited in the literature. Although there is evidence (6) that there may be differences in steroid hormone levels between White and African-American women, in our study the association remained nearly identical after we controlled for some markers of steroid levels, such as age at menarche and oral contraceptive use. At the end of the 19th century, Balloch (23
) speculated about a tendency for "fibroid processes" to occur among African Americans, including elephantiasis, keloids, and UL. In fact, darker skin color is a predisposing factor to keloid formation, and a structural similarity between UL and keloids does exist, in that proliferated fibroblasts and collagencharacteristic of these dermal tumorsare also components of UL pathologic structure, together with smooth muscle cells (24
). Sex hormones seem to be related in unknown ways to keloids (which are reportedly more common in women than in men, and which may enlarge during pregnancy) and to melanocyte metabolism: Facial pigmented patches (melasma) develop in some women during pregnancy and with oral contraceptive use (17
), and these women apparently have a decreased risk of cutaneous melanoma (25
). These relations might somehow represent a link between hormonal exposures and predisposing factors associated with African-American heritage, such as darker skin color, that are perhaps also involved in UL development. In addition, in accordance with our "atherogenic" hypothesis (20
), a higher risk among African-American women might also be influenced by hyperinsulinemia.
Regarding associations with markers of hormonal exposure, the results of the present study were in partial agreement with previous research. The association between UL risk and early menarche, which was also suggested by previous studies (7, 9
, 11
, 12
), bears two alternative explanations, and perhaps both are valid. It has been suggested that early menarche is associated with higher estrogen levels throughout reproductive life (26
), although direct evidence for this is lacking (27
). On the other hand, menarche at a younger age implies earlier establishment of regular ovulation (28
) and thus more prolonged exposure to both estrogen and progesterone.
The specificity of the UL associations with parity (inverse) and infertility (positive) to cases with submucous tumors constitutes suggestive evidence in favor of relative infertility and consequent lower parity being primarily a consequence of UL. Our analyses had clear limitations in addressing these relations, because information on tumor location was missing for two thirds of the cases; however, associations of UL with parity and infertility showed similar patterns when cases with known tumor locations were compared with those with missing information.
Because submucous tumors tend to protrude into the uterine cavity, they are more likely to interfere with ovum implantation and the normal progression of pregnancy. In fact, UL may emerge as the sole abnormality in patients undergoing infertility evaluation (17), and women with UL have an increased risk of spontaneous abortion (17
). If infertility were a risk factor for UL development, either due to underlying hormonal imbalances or through its impact on parity, no such specificity of these associations with submucous tumors should have been detected. In other words, cases would show a higher proportion of births at younger ages because growing tumors would tend to induce infertility, thus interfering with the frequency of births at later ages, not because full term pregnancies themselves or full term pregnancies at given ages have a protective effect. In most previous studies, the inverse association with parity (7
10
) and the positive association with infertility (10
) may have resulted from the restriction of cases to surgical cases, consisting predominantly of larger tumors. However, this interpretation cannot explain findings from the Nurses' Health Study (11
), where those associations were present when both surgical and nonsurgical UL cases were considered.
The risk of UL was found to be greatly decreased with current oral contraceptive use, and less so with former use. Negative associations with aspects of oral contraceptive use were also found in some previous studies (8, 9
, 13
) but were not observed in others (7
, 11
). It has been suggested (13
, 29
) that a negative association with current use might arise because physicians would have advised patients to discontinue oral contraceptives once UL was diagnosed or suspected. In our study, the possible impact of such a situation was shown to be negligible, as there were few instances in which discontinuation was reportedly related to suspicion or diagnostic confirmation of UL.
The negative association of UL with oral contraceptive use has also been interpreted (8) as supporting the unopposed estrogen theory, because of the absence of uterine exposure to unopposed estrogen characteristic of the physiologic proliferative menstrual phase. However, an alternative interpretation is that a protective effect results from the "flattening out" of both estrogen and progesterone levels associated with oral contraceptive use, which reduces myometrial exposure to these hormones. The possibility remains that an underlying hormonal state is associated with both UL risk and incompatibility with oral contraceptive use.
We observed a twofold increased UL risk among women in the upper quartile of body mass index; this association was also present in other studies (8, 9
, 12
, 14
), but not in all (7
, 16
). The association of obesity with hormone-related gynecologic conditions tends to be attributed to a hyper-estrogenic milieu (8
). Among premenopausal obese women, most studies do not show an increase in circulating concentrations of estrogens, probably because ovarian production minimizes this peripheral contribution (30
); however, bioavailable estrogen would still increase because of decreased concentrations of sex hormone-binding globulin (8
). In addition, it is also conceivable that nonhormonal determinants, such as hyperinsulinemia, partly explain the association of UL with obesity (20
).
In this study, smoking for approximately 20 years or more was associated with a 40 percent decreased risk of UL in comparison with nonsmoking. Smoking is considered to be associated with an estrogen-deficient state, through disturbed gonadotropin release or enhanced formation of inactive estrogen from estradiol, among other postulated mechanisms (31). A negative association of UL with some aspect of smoking history was found in most previous studies (7
, 8
, 15
, 16
), with the exception of the Nurses' Health Study (14
). Although body mass index and smoking history are generally inversely related, we did not detect patterns of mutual confounding or effect modification between these characteristics in our data.
In a case-control study of a condition with UL characteristics, the possibilities of selection bias and recall bias should be discussed. Attempts were made at the design stage of this study to minimize the possible impact of selection bias by including nonsurgical cases, thus avoiding the restriction of inferences to a possibly select subset of cases. In addition, participation rates were similarly high for cases and controls.
The selection of practice-based controls was considered an appealing strategy for increasing the likelihood that cases and controls would originate from the same source population. A potential drawback of practice-based studies is that exposures may be associated with the controls' related conditions (32). This study took advantage of the fact that not only patients with specific conditions but also many healthy women periodically visit their gynecologists for routine evaluation and screening.
Misclassification in the control group due to the inclusion of undiagnosed cases is a reason for concern in studies of common conditions like UL. We reduced the likelihood of this problem by including as potential controls only those who, besides having no history of suspected or confirmed UL, had a normal pelvic examination as part of a routine medical visit. However, the possibility of selection bias resulting from the characteristics of the controls deserves close scrutiny. Some of these controls might represent a highly health-conscious group who keep regularly scheduled routine gynecologic visits; among these women, the prevalence of some exposures (e.g., smoking, obesity) may be lower than that in the study base. Alternatively, controls exposed to some study variables (e.g., oral contraceptive users) might actually need to be more closely monitored.
In both scenarios, differential health behavior and frequency of gynecologic monitoring, if associated with study exposures, might have resulted in detection bias. However, when analyses were repeated after the exclusion of participants with less than one gynecologic visit per year and less than one dental visit per year, we observed that only the association with being African-American was importantly affected, denoting a strong negative confounding effect of those characteristics.
To further assess the possibility of detection bias, we conducted additional analyses after excluding cases who had no typical symptoms prior to diagnosis; these analyses were aimed at assessing the possibility that, among these cases, certain characteristics (e.g., being African-American) might have heightened diagnostic suspicion of UL among gynecologists. To investigate whether the inclusion of misdiagnosed cases could reasonably be ruled out as a source of bias in this study, we refitted logistic regression models after excluding cases whose diagnostic confirmation had been based on a single uterine sonogram. Estimates were virtually unchanged in both situations.
The high agreement between data obtained from interviews and data obtained from medical records, which was similar for cases and controls, suggests an overall good quality of recall, although these analyses were based only on age at menarche; even more importantly, it indicates a high degree of recall similarity between cases and controls.
Because of sample size limitations, we were unable to conduct analyses restricted to African-American women or to surgical cases only. In addition, we found no indication that ethnicity was an effect modifier of the other study associations, but these analyses were hampered by small numbers.
In conclusion, this study confirmed the existence of a substantially higher risk of developing UL among African-American women compared with White women. In addition, our findings suggest that markers of exposure to increased levels of both estrogen and progesterone are likely to be involved in UL development. Some biologic pathways were discussed above; other possible mechanisms, including the roles of androgens and of hormonal changes associated with pregnancy, have been reviewed by Marshall et al. (11).
A possibly fruitful and cost-effective strategy for future epidemiologic research on UL would be to include baseline and follow-up pelvic sonograms in a sample of participants in prospective studies, and to measure sex steroid levels in addition to collecting data on medical and reproductive history. We would also recommend longitudinal studies of women attending infertility clinics, to take advantage of information on specific causes of infertility and on hormone levels which is generally available for these patients. Preferably, these should be studies of populations with enough ethnic and socioeconomic variability to allow evaluation of the roles of these factors.
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ACKNOWLEDGMENTS |
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The authors are indebted to the gynecologists who allowed them to recruit participants from their patient populations. The authors also thank Dr. Kathy Helzlsouer, Dr. George Comstock, and Joel Hill for helpful suggestions, and the research assistants who helped with the fieldwork: Dr. Tania Loes, Barbara Martin, Kera Weiserbs, Dr. Alba Benaque, Beryl Carew, Nancy Carey-Beaver, Kimberly Mackin, Paula Platt, Lane Cameron, Kelli Garrity, Tae Kim, and Gilbert Gee.
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NOTES |
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Editor's note: An invited commentary on this two-part paper and on the following article by Chen et al. appears on page 27.
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REFERENCES |
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