Risk Factors for Uterine Leiomyoma: A Practice-based Case-Control Study. II. Atherogenic Risk Factors and Potential Sources of Uterine Irritation

Eduardo Faerstein1, Moyses Szklo2 and Neil B. Rosenshein3

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.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this case-control study, the authors analyzed associations of uterine leiomyoma with atherogenic risk factors and potential sources of uterine irritation. The study included 318 case women with uterine leiomyoma that was first confirmed between 1990 and 1993 in the Baltimore, Maryland, area and 394 controls selected from women visiting the same gynecologists' offices for routine reasons. Telephone interviews were conducted with 77.8% of eligible cases and 78.0% of eligible controls. Compared with participants with no hypertension history, increased risks were observed among participants with any history of hypertension (odds ratio (OR) = 1.7; 95% confidence interval (CI): 1.0, 2.8), hypertension requiring medication (OR = 2.1; 95% CI: 1.1, 4.1), hypertension diagnosed at ages less than 35 years (for hypertension requiring medication, OR = 2.7; 95% CI: 1.0, 7.6), and hypertension of 5 or more years' duration (for hypertension requiring medication, OR = 3.1; 95% CI: 1.2, 8.2). Estimates of associations with diabetes history were very imprecise but followed similar patterns. Adjusted associations were observed with pelvic inflammatory disease (three or more episodes vs. none: OR = 3.7; 95% CI: 0.9, 15.9), chlamydial infection (history vs. no history: OR = 3.2; 95% CI: 0.8, 13.7), and use of an intrauterine device when it caused infectious complications (use vs. no use: OR = 5.3; 95% CI: 1.8, 16.3). Risk of uterine leiomyoma was also associated in a graded fashion with frequency of perineal talc use (daily use vs. no use: OR = 2.2; 95% CI: 1.4, 3.1). The authors conclude that nonhormonal factors may influence risk of uterine leiomyoma.

adnexitis; case-control studies; hypertension; intrauterine devices; irritants; leiomyoma; risk factors; uterine diseases

Abbreviations: CI, confidence interval; IUD, intrauterine device; PID, pelvic inflammatory disease; UL, uterine leiomyoma


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Uterine leiomyomas (ULs), also known as fibroids, are the most common pelvic tumors. Most cases are asymptomatic, but patients frequently have local symptoms, infertility, and adverse pregnancy outcomes (1Go). In several countries, UL is the leading cause of hysterectomy, accounting for one third to one half of these surgeries (2Go, 3Go).

Published results from the few contemporary epidemiologic studies that have been conducted emphasize associations with reproductive history and markers of exposure to steroid hormones (4GoGoGoGoGoGoGoGo–12Go) and ethnicity (6Go, 13Go). Although the results of previous work are partially conflicting, they suggest that levels of ovarian hormones influence UL risk. In a companion paper (14Go), in addition to the strong association of UL risk with African-American ethnicity, we report relations between UL and selected characteristics associated with endogenous and exogenous hormone levels. According to experimental and clinical evidence (15Go), exposures to estrogen and progesterone seem to be of etiologic importance.

Interestingly, there is some suggestion of similarities between a tumor of smooth muscle cells like UL and the atheromatous plaque. A key event in plaque formation is also smooth muscle cell proliferation, which is induced by atherogenic risk factors such as hypertension and diabetes mellitus (16Go). UL has a monoclonal origin (17Go), which has also been postulated for the atheromatous plaque (18Go, 19Go); cells from both conditions behave identically in culture (20Go). Uterine smooth muscle cells in toxemia of pregnancy can accumulate intracytoplasmic lipid, simulating the basic structure of the atheromatous lesion (21Go).

A coexistence of UL with hypertension was noted in several small studies conducted between the 1930s and the 1970s (22GoGoGoGoGo–27Go). Some authors (24Go, 27Go), but not all (25Go), observed that the association persisted after data were controlled for weight. Although it has been suggested that UL would cause hypertension as a consequence of urinary tract obstruction by large tumors (23Go, 26Go), this reverse-causality interpretation has been questioned (27Go).

Along other lines, the observed coexistence of UL with pelvic inflammatory disease (PID) (28Go) supports a possible role of local irritation in the development of these tumors. Infectious processes or chronic inflammatory processes have been found to be associated with the development of several neoplasms (29Go, 30Go). For example, children infected with human immunodeficiency virus have increased incidence of both leiomyoma and leiomyosarcoma in several organs (31Go, 32Go). The potential role of infection in UL development can also be postulated in the context of similarities between this tumor and the atheromatous plaque, because of the suggestion that chlamydial and viral infections play a role in atherosclerosis (33Go, 34Go).

In addition to behavioral aspects of sexual life, other factors may predispose women to ascending infections of the genital tract. Use of an intrauterine device (IUD) induces a local inflammatory reaction and is associated with bacterial vaginosis, endometritis, and PID (35Go, 36Go). Thus, a possible association of UL with IUD use might result from its status as a marker of clinical or subclinical uterine infection, or from a direct irritational effect. A possible irritational effect may also result from perineal use of talc. To date, ovarian cancer has been the only neoplasm studied in relation to this personal habit, and some authors (37Go), though not all (38Go), have concluded that a causal association is likely.

The aims of this interview-based case-control study included an exploration of these hypotheses. We assessed the possible role of atherogenic risk factors by examining associations of UL with self-reported, physician-diagnosed hypertension and diabetes. To test the irritational hypothesis, we explored associations with common sources of potential uterine irritation: self-reported, physician-diagnosed PID and chlamydial infection as recorded on medical charts, and self-reported use of IUDs and perineal talc.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study's methods are described in more detail in the companion paper (14Go). Briefly, the study population comprised premenopausal female residents of the Baltimore, Maryland, Standard Metropolitan Statistical Area (Baltimore City and six surrounding counties). Cases were women with UL (International Classification of Diseases, Ninth Revision, code 218) that was first diagnosed by one of 17 collaborating gynecologists between 1990 and 1993. Diagnosis had to have been confirmed by histologic findings (surgical cases) or at least one uterine sonogram. 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. No controls developed clinically detectable UL during the study period.

Telephone interviews were conducted between February and October of 1994 by trained study personnel. Cases and controls were asked to provide information on sociodemographic characteristics; medical history of hypertension and diabetes; menstrual, reproductive, and infertility history; use of oral contraceptives and IUDs; perineal use of talc and vaginal douching; history of PID; family history of hysterectomy due to UL; smoking history; height and body weight; and frequency of dental checkups. Body mass index was calculated as weight (kg) divided by height squared (m2).

Abstraction of medical records was carried out no later than 2 weeks after the interview. Abstractors were not told of the study-specific hypotheses, and they abstracted controls' and cases' charts in similar ratios. We conducted an independent abstraction of a systematic sample (20 percent) of medical records.

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 (Pap) smears, PID, sexually transmitted diseases, benign breast disease, endometriosis, and endometrial hyperplasia. Additional data abstracted from cases' charts were: presence of typical symptoms 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; reported number of tumors; and diameters of the three largest reported tumors and their location within the uterus (submucous, intramural, or subserous).

After conducting an initial assessment of confounding effects and effect modification through stratified analyses that included all relevant study variables, we used unconditional logistic regression models, fitted by the method of maximum likelihood, to simultaneously adjust for confounding. For each study exposure, we fitted a first model that included age and clinic, used for frequency-matching the study groups. A second model was built with all potential confounders included, and this was followed by sequential cycles of variable deletion utilizing the "change-in-estimate" approach (39Go): 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 this paper, we refer throughout the text to the adjusted estimates obtained using the second models. The resulting models were additionally checked with selective exclusions of subsets of participants so that the likelihood of selection and misclassification biases could be explored, and with the inclusion of variables thought a priori to be potential confounders. When appropriate, we conducted trend tests by assigning the midpoints of the categories as data points and treating the scored variables as continuous.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In our companion paper (14Go), we reported some characteristics of cases and controls, in addition to clinical and pathologic features of the case series; we also reported results regarding two atherogenic factors, smoking and body size. In this paper, we report on two additional factors related to atherosclerosis—hypertension and diabetes—as well as exposures potentially related to uterine irritation.

Hypertension and diabetes mellitus
Respondents with a history of hypertension had a 1.7-fold adjusted risk of UL (95 percent confidence interval (CI): 1.0, 2.8) (table 1). Among women reporting a history of hypertension for which medication was prescribed, the adjusted risk of disease was 2.1-fold that of participants without such a history (95 percent CI: 1.1, 4.1).


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TABLE 1. Distributions of cases with uterine leiomyoma and controls and adjusted odds ratios for uterine leiomyoma, according to hypertension history variables: Baltimore, Maryland, 1990–1993

 
Mean age at hypertension diagnosis was slightly lower among cases than among controls; differences were larger when only hypertension requiring prescribed medication was considered. Compared with women who had never been diagnosed with hypertension, a 1.8-fold adjusted risk (95 percent CI: 0.9, 3.7) of UL was observed for those who were under age 35 years when first diagnosed. A higher, 2.7-fold risk was observed for those who were under age 35 when first diagnosed with hypertension requiring prescribed medication (95 percent CI: 1.0, 7.6).

Cases had a higher mean duration of hypertension than controls; a larger mean difference was observed with the more stringent definition which included only those taking antihypertensive medication. Participants with a known hypertension duration of >=5 years had a 2.1-fold increased adjusted risk of UL (95 percent CI: 1.0, 4.1) compared with women without a history of hypertension; the excess risk was 3.1-fold when only hypertension requiring medication was considered (95 percent CI: 1.2, 8.2). The independent contributions of age when first diagnosed and duration of hypertension could not be explored because of high collinearity between these two variables.

Prevalences of self-reported physician-diagnosed diabetes were 4.7 percent and 4.1 percent among cases and controls, respectively (table 2); because numbers of cases and controls reporting diabetes were small, odds ratio estimates had wide confidence intervals. Similarly to hypertension history, a more stringent definition of diabetes history was also explored based on whether oral medication or insulin had ever been prescribed, to exclude transient episodes (e.g., gestational diabetes) and to increase the specificity of exposure definition.


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TABLE 2. Distributions of cases with uterine leiomyoma and controls and adjusted odds ratios for uterine leiomyoma, according to diabetes history variables: Baltimore, Maryland, 1990–1993

 
No association of UL with history of physician-diagnosed diabetes was observed using the standard definition (table 2). However, diabetes requiring medication was associated with a nonsignificant twofold adjusted excess risk. On average, cases were younger than controls when diabetes was first diagnosed and had a longer duration of diabetes. Numbers were too sparse for us to explore trends according to age at diabetes diagnosis or diabetes duration. However, three out of seven case women with diabetes requiring medication (43 percent) and no control women had been diagnosed before age 35; four out of seven cases (57 percent) and no controls had medication-requiring diabetes of 5 or more years' duration. The only control woman who reported insulin use was 51 years old and had been on medication for less than 1 year, whereas all three case women using insulin were in their mid-thirties or mid-forties and had been taking insulin for more than 10 years (data not shown in table).

Virtually no changes were observed when the logistic regression model, in addition to hypertension, diabetes, age, clinic, ethnicity, and body mass index, also included terms for educational level, marital status, maternal history of hysterectomy due to UL, smoking duration, parity, and oral contraceptive use. Estimates remained nearly identical when we conducted additional analyses to evaluate the likelihood of detection bias. These analyses selectively excluded 1) cases with no typical UL symptoms prior to diagnosis, 2) participants with less than one gynecologic visit per year, and 3) participants with less than one dental visit per year. When cases with lesser diagnostic certainty (confirmation based on a single sonogram) were excluded, the only noticeable change was the strengthening of the associations with hypertension.

Histories of PID and sexually transmitted disease and use of IUDs and perineal talc
A 1.8-fold increased adjusted risk of UL was found among women who reported a history of physician-diagnosed PID (95 percent CI: 1.0, 3.1) (table 3). The analyses excluded several episodes of PID that had occurred after UL diagnosis. Cases reported a higher median number of PID episodes than controls, and there was a clear-cut linear trend in odds ratios with number of past PID episodes (trend test: p < 0.001). The adjusted risk was increased 3.7-fold (95 percent CI: 0.9, 15.9) among participants who reported three or more past episodes compared with those who had never had PID.


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TABLE 3. Distributions of cases with uterine leiomyoma and controls and adjusted odds ratios for uterine leiomyoma, according to history of pelvic inflammatory disease, several sexually transmitted diseases, and abnormal Pap smears: Baltimore, Maryland, 1990–1993

 
Adjusted estimates showed no statistically significant associations with genital herpes or warts. However, chla-mydial infection was associated with a 3.2-fold increased risk of being a case, although this estimate was imprecise and the 95 percent confidence interval overlapped unity (95 percent CI: 0.8, 13.7). A negative association of UL with history of abnormal Pap smears was observed; participants with such a history had half the risk of being a case.

No consistent associations were observed between UL and status or duration of IUD use (table 4). Additional analyses were based on verbatim information provided by former users on their reasons for IUD discontinuation; the only group of reasons for which cases (20Go) and controls (5Go) differed substantially was "infections," "fever," or "discharge." When only those situations were considered, the odds ratio associated with former use was 5.3 (95 percent CI: 1.8, 16.3) in comparison with never use (data not shown).


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TABLE 4. Distributions of cases with uterine leiomyoma and controls and adjusted odds ratios for uterine leiomyoma, according to variables related to use of intrauterine devices and perineal talc: Baltimore, Maryland, 1990–1993

 
UL risk was increased twofold and 70 percent among participants who reported, respectively, former and current application of talc to the genital area or to sanitary pads (table 4). Positive associations were consistently observed across levels of frequency and duration of use; most confidence intervals did not overlap unity. Although no clear-cut pattern of risk was observed across categories of duration of use, adjusted estimates suggested a graded association between frequency of use and UL risk (linear trend: p < 0.001).

All of the above findings were almost unchanged after we made selective exclusions of: 1) cases who had had a single diagnostic sonogram and no reported typical symptoms at the medical visit prior to diagnosis; 2) participants who had had less than one gynecologic visit per year, on average, during the previous 3 years; and 3) those who reported usually having less than one dental visit per year. The only noticeable changes were attenuations of the association between UL and former talc use after exclusion of subjects with less than one gynecologic visit per year (from an odds ratio of 2.1 to an odds ratio of 1.6) and subjects with less than one dental visit per year (from an odds ratio of 2.1 to an odds ratio of 1.4).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
With regard to the atherogenesis hypothesis, anecdotal reports have linked hypertension to UL (22GoGoGoGoGo–27Go). The present study provides controlled evidence of an association between UL risk and hypertension.

This association might have resulted from bias if hypertensive patients had been encouraged by their clinicians to have routine gynecologic checkups, which in turn may have led to a higher probability of asymptomatic tumor diagnosis in cases than in controls. By the same token, UL patients, with a higher frequency of gynecologic visits than controls, would have had more opportunities for detection of asymptomatic hypertension. However, exclusions of participants with less than one gynecologic visit per year and (in a broader context of health care habits) those with less than one dental visit per year had minor effects on the estimates. Finally, estimates were also virtually unchanged after exclusion of UL cases without typical symptoms prior to diagnosis, which provides additional evidence against the presence of substantial detection bias.

In addition to ethnicity and body mass index, parity was considered an important potential confounder of the association of UL with hypertension, because patients with preeclampsia are at increased risk of chronic hypertension later in life (40Go). Furthermore, because blood pressure measurement is part of standard prenatal care, parous women are also more likely to be diagnosed with hypertension. However, this potentially confounding effect was not observed in our data. In any case, the more stringent definition based on whether medicine has ever been prescribed for hypertension tends to exclude transient pregnancy-induced episodes, because only a small proportion of those patients (that is, those developing severe eclampsia) will have required antihypertensive medication. Use of oral contraceptives is another potential confounder, because hypertension is a contraindication for oral contraceptive use, and users must discontinue use once hypertension has been diagnosed (41Go). However, analyses of the UL-hypertension association which took oral contraceptive use into consideration showed no confounding effect.

The most frequent interpretation for the association between hypertension and UL has been reverse causality, through compression of the urinary tract by an expanding uterine mass (23Go, 26Go); yet evidence provided by this study favors the idea that hypertension most commonly precedes UL. Under reverse causality, a stronger association would be expected among persons diagnosed with hypertension more recently and at older ages. However, the adjusted association was confined to women who had had diagnosed hypertension for 5 or more years, and it was stronger among those who were under age 35 at hypertension diagnosis. In addition, associations were stronger with hypertension requiring medication; this may reveal a higher risk of UL among persons exposed to more clinically severe hypertension.

In the present study, imprecise estimates preclude firm inferences about a possible association of UL with diabetes. It is notable, however, that even with such small numbers, a pattern similar to the association of UL with hypertension was observed—namely, higher proportions of cases had more severe diabetes, were younger at diabetes diagnosis, and had diabetes of longer duration. This similarity suggests that there might have been an association of UL with diabetes in this study's source population, but the study did not have enough statistical power to detect it.

Hyperinsulinemia is a natural candidate for a possible pivotal role which would provide a biologically plausible link between hormone-related and atherogenic determinants. Firstly, insulin resistance and hyperinsulinemia have been proposed as possible mechanisms underlying pathophysiologic pathways connecting obesity (which was associated with UL in our study (14Go)), diabetes, hypertension, and hyperlipidemia, eventually leading to atherosclerosis (42Go). Secondly, insulin has been shown to promote cell mitosis (43Go), to promote vascular smooth muscle proliferation in rats (44Go), and, in particular, to stimulate the growth of UL cells in tissue culture (45Go). Finally, it has been suggested that insulin may have a specific gonadotropic function, stimulating ovarian secretion via insulin receptors or receptors for insulin-like growth factors (46Go). Thus, hyperinsulinemia may influence UL development through direct promotion of myometrial smooth muscle cell proliferation or by increasing circulating levels of ovarian hormones.

In addition to the atherogenic hypothesis, the present study also assessed the association of UL with potential sources of uterine irritation. A graded association of UL with number of self-reported PID episodes was observed. The possibility of an association of UL with PID was raised several decades ago (47Go) but apparently was not adequately tested. In the Oxford Family Planning Association Study (4Go), the frequency of PID was very low, but there was some indication that it was higher among UL cases than among controls. An effect of infectious agents on myometrial tissue seems plausible because of the growing body of evidence relating infectious agents to several neoplasms (29Go), and more specifically because of the observed development of smooth muscle neoplasms among children infected with human immunodeficiency virus (48Go). A possible relation between uterine infections and UL is also suggested by the association of UL with chlamydial infection, a common cause of PID (49Go), but not with infections (such as genital herpes) which affect mostly the external genitalia. On the other hand, the inverse association of UL with abnormal Pap smears was probably due to the frequent and long term monitoring needed for patients who had ever had those abnormalities; hence, women with such a history might have been overrepresented among the controls, whereas most of the cases had visited the gynecologists because of UL symptoms.

Previous reports on the association between IUD use and UL have been limited and conflicting (4Go, 6Go, 7Go). In the current study, overall results did not show an association of UL with IUD use; however, the fivefold increased risk detected when IUD use had reportedly been discontinued because of infectious complications might be considered further evidence for an etiologic role of local infection.

An association was found between UL and perineal talc use, with suggestions of a dose-response gradient in relation to frequency of use. Excessive menstrual flow, theoretically a possible motivation for talc use, did not show a confounding effect. Reverse causation is another possibility: Talc could be used because of excessive bleeding due to undiagnosed UL. However, participants were asked to report their frequency of use when they had first started using talc; the smallest odds ratio was associated with the shortest category of duration of use (data not shown); and cases had started using talc, on average, at age 20, which is very distant in time from the mean age at UL diagnosis (42 years).

In general, our data support the hypothesis that local uterine irritants of infectious or noninfectious origin may play a role in UL development, either because endometrial inflammation induces a myometrial response or because both endometrial and myometrial tissues are directly involved, as sometimes occurs (endometritis-myometritis) in situations such as puerperal sepsis (49Go).

The overall stability of the results after selective exclusions of subsets of participants favors the idea that selection and misclassification biases are not likely explanations for these findings. This study's limitations include its retrospective nature and crude assessment of some of the exposures of interest, involving no direct measurements. While recall bias resulting in important differential misclassification of exposures does not seem to be a likely explanation for our results (14Go), nondifferential misclassification due to the nature of data obtained from interviews and medical charts may have resulted in the attenuation of some associations.

Our results suggest that epidemiologic and experimental work related to UL etiology should be expanded beyond the hormonal paradigm. The atherogenesis hypothesis should be submitted to more severe testing. Thus, future studies should include direct measurements of blood pressure, lipid levels, glucose tolerance, and insulin resistance. In addition, the possible dual role of smoking—which is both an estrogen suppressor, thus decreasing risk (see companion paper (14Go)), and an atherogenic factor—should be further clarified. If the irritational hypothesis is addressed, measurement of antibodies to sexually transmitted diseases would be of interest. It might also be worthwhile to explore the potential role of other sources of uterine trauma, such as cesarean section and dilation and curettage. In vitro studies could evaluate the effect of a variety of atherogenic and potential irritants on UL initiation and growth, and would constitute powerful tests of the hypothesis that nonhormonal factors are also involved in the development of these tumors.


    ACKNOWLEDGMENTS
 
This work was supported by grants from the Brazilian Ministries of Education (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and Health (Instituto Nacional de Câncer), the State University of Rio de Janeiro, and the National Cancer Institute/National Institutes of Health Small Grant Program (Award 1RO3CA197501). Additional support was provided by the Summer Program in Epidemiology and the Department of Epidemiology, School of Hygiene and Public Health, Johns Hopkins University (Baltimore, Maryland).

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.


    NOTES
 
Correspondence to Dr. Eduardo Faerstein, Universidade do Estado do Rio de Janeiro, Rua Sacopã, 191 apto 201, 22471-180 Rio de Janeiro, RJ Brazil (e-mail: eduardof{at}uerj.br).


    REFERENCES
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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Received for publication December 12, 1997. Accepted for publication March 14, 2001.