Body Mass Index at Age 18 Years and during Adult Life and Ovarian Cancer Risk

F. Lubin1,, A. Chetrit1, L. S. Freedman2, E. Alfandary1, Y. Fishler1, H. Nitzan1, A. Zultan1 and B. Modan3,4

1 Cancer Epidemiology Unit, Gertner Institute, Sheba Medical Center, Tel Hashomer, Israel.
2 Biostatistics Unit, Gertner Institute, Sheba Medical Center, Tel Hashomer, Israel, and Bar Ilan University, Ramat Gan, Israel.
3 School of Allied Health Sciences, Ariel College, Ariel, Israel.
4 Stanley Steyer Institute for Cancer Epidemiology and Research, Tel Aviv University Medical School, Tel Aviv, Israel.

Received for publication September 7, 2001; accepted for publication August 9, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
During the years 1994–1999, a nationwide ovarian cancer case-control study was conducted in Israel. The present analysis addresses the question: Is epithelial ovarian cancer associated with body mass index at age 18 years and/or with weight changes in body mass index between adolescence and adult life? The study is based on 1,269 women with epithelial ovarian cancer and 2,111 matched controls. A significant decrease in risk of ovarian cancer was observed with parity, oral contraceptive use, and postmenopausal status. A significant increase in risk with family history of ovarian/breast cancer was also found. No significant association with age at menarche or infertility was found. For body mass index at age 18 years, the odds ratio of the highest versus lowest body mass index quartile was 1.42 (95% confidence interval: 1.08, 1.85) and after adjusting for confounders was 1.54 (95% confidence interval: 1.17, 2.02). However, no statistically significant risk associated with change in weight from age 18 years to adult life was found. The authors conclude that, in their population, body mass index at age 18 years is an independent risk factor for ovarian cancer.

body mass index; ovarian neoplasms; risk


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ovarian cancer accounts for 4–5 percent of all female cancer cases in Israel and about a quarter of all cancer deaths in women. In 1995, the age-adjusted incidence and mortality rates per 100,000 among Israeli Jewish women were 12.9 and 9.4, respectively. The reported incidence rate among Israeli non-Jewish women was only 3.0 (1).

The main established risk factors for ovarian cancer are family history (2, 3), low parity (2, 4), and oral contraceptive use (protective) (5, 6). Infertility (7), age at menarche, and menopause were also studied in association with ovarian cancer risk (4, 8). Several epidemiologic studies have reported a positive association between body mass index and ovarian cancer risk in diverse populations (813). In this paper, we investigate the relation between body mass index and ovarian cancer in more depth, particularly with reference to age.

Weight, height, and body mass index have been found to be associated with hormonally related cancers, especially breast cancer. The biologic theories proposed for the link between body mass index and other hormone-related morbidity in women are also relevant to ovarian cancer etiology (1417). Risch (18), among others, postulates that excess androgenic stimulation of ovarian epithelial cells through gonadotropin stimulation results from incessant ovulation or increased gonadotropin excretion. He suggests that factors associated with excess androgenic stimulation of ovarian epithelial cells may increase the risk of ovarian cancer, and that factors related to greater progesterone stimulation may decrease it. Increased body mass index is directly associated with increased adipose tissue, which may induce ovarian and extraovarian estrogen production.

Overweight at puberty may stimulate androgenic secretion of estrogens at a time of life when progesterone levels are still low (19). Indeed, since the major progesterone increase in women occurs only after the first pregnancy, overweight before the first pregnancy may be particularly important in ovarian cancer risk. Once initiated, the process may be continued by adiposity maintained during adulthood. The deleterious effect of obesity in young adult life on other aspects of ovarian hormonal function is exemplified by the associations between overweight and infertility and between overweight and polycystic ovarian syndrome (2027).

In addition, a study conducted in England and Wales found that women who died of ovarian cancer had high rates of weight gain in infancy that were not explained by the way they were fed. Based on follow-up of above 5,000 women, the authors suggest that the origins of ovarian cancer lie in hormonal influences, which imprint and alter the pattern of gonadotropin release, promoting infant weight gain (28).

In this paper, we make use of data on body mass index reported for two ages: age 18 years, representing the end of physiologic growth or puberty, and "most of adult life," representing average long-term exposure to overweight. To examine the hypotheses described above, we address the following questions. Is epithelial ovarian cancer associated with body mass index at age 18 years or with changes in body mass index between this period and adult life or both? Is any association between body mass index and ovarian cancer explained by known hormone-related risk factors, such as parity or oral contraceptive use? Finally, because recent reports have suggested that risk factors for ovarian cancer may differ between BRCA1 and BRCA2 mutation carriers and noncarriers (2), we examine this question in relation to body mass index.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
During the years 1994–1999, a nationwide ovarian cancer case-control study was conducted in Israel. All Jewish patients with newly diagnosed ovarian cancer were identified in the 22 gynecologic departments in Israel during this period. Only histologically verified cases were included. In total, 1,707 incident ovarian cases were diagnosed, of which 1,269 were of the epithelial type. Of these 1,269 cases, 233 were of borderline type, and 1,036 were invasive. The present analysis is limited to the epithelial ovarian cancer cases and 2,111 matched controls.

We identified two population controls per case, individually matched for age (within 2 years), origin (country of birth), place of residence, and immigration period (before 1948, 1948–1967, 1968–1987, and after 1987) using stratified random sampling according to the matching demographic characteristics, drawn from the Central Population Registry. However, because of technical reasons, for cases identified during the last year of data collection, only one matched control was selected. The response rate was 79 percent for cases and 66 percent for controls.

All cases and controls were interviewed after informed consent had been obtained. A second informed consent to conduct a genetic test was obtained by the patient’s gynecologist. Tests were performed at the Laboratory of Population Genetics of the US National Cancer Institute. The study was approved by our institutional review board and by a National Cancer Institute ethics panel.

Patient identification and specimen collection
Study nurses were in regular telephone and personal contact with all the gynecologic departments in Israel to identify new ovarian and peritoneal cancer cases. Pathology and oncology department records were screened periodically to check for completeness of case identification. The nurses abstracted clinical information from patients’ medical records and collected surgical and pathologic reports. Pathology specimens and blood samples for further confirmation of diagnosis and genetic testing were also collected.

Personal interviews
Interviews were conducted by a group of experienced and specially trained multilingual interviewers. Training of the interviewers included didactic instruction on the goals of the study, administration of the questionnaire, and interviewing techniques. Most of the cases were interviewed while hospitalized, typically between the fourth and sixth days after surgery. A limited number were interviewed at home.

Population controls were interviewed at home after telephone contact to schedule the interview. To increase the response rate, if no telephone contact could be established, interviewers performed at least three home visits before the first control was replaced. Interviews lasted more than 1 hour. When needed, for new Russian immigrants, the interview was conducted in Russian, by Russian-speaking interviewers using translated questionnaires.

The questionnaire included the following information: demographic and socioeconomic characteristics; smoking habits; family history of cancer; reproductive history; infertility; length of use of oral and other contraceptives; other hormone-related information (age at menarche, age at menopause, length of menstrual cycles, menstrual irregularities, use of hormone replacement therapy); gynecologic morbidity and procedures, as well as other morbidity; weight at age 18 years, during "most of adult life," and "recently" (before illness for cases and 1 year before interview for controls); and height at end of growth.

Laboratory methods
Genetic testing began in the second year of the study and therefore was not available for all subjects. BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutation tests were performed in 70.6 percent of the cases, using genetic laboratory techniques that have been described previously (2). Biologic samples available for testing included peripheral blood and paraffin-embedded tissue sections.

Statistical methods
We first investigated the individual effects of family history of either breast or ovarian cancer in first-degree family members, ever use of oral contraceptives, parity, menopausal status, age at menarche, and infertility problems requiring treatment on ovarian cancer risk.

Not all subjects reported a value for past body weight. For body weight at age 18 years, 74.3 percent of the subjects reported a value, whereas 91.8 percent reported a value for weight during "most of adult life." Analysis of body weight included only individuals with reported values.

Body mass index was calculated by weight (kg)/height (m)2 in each life period. Differences between cases and controls in weight and body mass index in each life period were first evaluated by t tests. In the main analyses, because of the matched study design, conditional logistic regression was used (29).

On the basis of the continuous distribution of the controls’ body mass index, at each life period separately, four levels of body mass index (quartiles) were determined. Odds ratios associated with the quartile of body mass index were estimated using the lowest level as the reference category. Corresponding 95 percent confidence intervals were derived, and linear trends were tested for significance. The same was done for change in body mass index from age 18 years to adult life. We then entered both body mass index at age 18 years and body mass index change together into the logistic regression model to identify whether they were independent risk factors. In the final analysis, we adjusted the effect of body mass index at age 18 years for the confounders mentioned above.

Because of the very low number of genetic tests performed among controls, we used case-case analysis (30) to evaluate interactions between body mass index and the BRCA1 and BRCA2 mutations.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 shows the demographic characteristics of the study population and the histologic types of ovarian cancers. As expected from the matched case-control study design, there are no significant differences between cases and controls with respect to age at diagnosis, year of immigration, or origin. Thirty percent of cases are below age 50, and 70 percent are of European-American origin. Eighteen percent of the cases have tumors of borderline malignancy. Table 2 shows the odds ratios for ovarian cancer associated with the known main hormone-related factors. Increased parity, oral contraceptive use, and postmenopausal status are significantly inversely associated with ovarian cancer risk, whereas family history is positively associated. No association with age at menarche or infertility is observed. The latter is possibly due to the relatively small group reporting infertility problems. Comparison of anthropometric characteristics of the cases and controls shows a statistically significant difference between cases and controls in mean weight and body mass index at age 18 years and during "most of adult life" (table 3). The same differences persist when analyzed by 10-year age category or by menopausal status at diagnosis (not shown). For example, the body mass index at age 18 years is 21.5 in premenopausal cases versus 20.9 in their controls (p = 0.01), and it is 21.8 in postmenopausal cases versus 21.3 in their controls (p = 0.001). No statistically significant differences between cases and controls in "recent" weight or body mass index are observed. Weight change (difference in weight from age 18 years to "most of adult life") appears similar among cases and controls. Further analysis focuses on the risk of ovarian cancer associated with body mass index at age 18 years and during "most of adult life."


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TABLE 1. Distribution of study population by demographic characteristics and histologic subtype of ovarian cancer, Israel, 1994–1999
 

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TABLE 2. Frequency distribution, odds ratios, and 95% confidence intervals of known risk factors and other hormone-related factors, Israel, 1994–1999
 

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TABLE 3. Distribution of study population by anthropometric characteristics at different life periods, Israel, 1994–1999
 
The conditional odds ratios and 95 percent confidence intervals for ovarian cancer associated with four levels of body mass index (lowest level as a reference category) at age 18 years and most of adult life show a statistically significant increase in risk at the highest body mass index level at both life periods (table 4). No significant risk with body mass index change is observed. To evaluate the relative importance of body mass index at age 18 years and later changes in adult life, we entered both factors into a multivariate model. Controlling for body mass index at age 18 years, we found that the odds ratios associated with each level of body mass index change were not significant. However, controlling for body mass index change, we found that the analysis confirmed the association between body mass index at age 18 years and ovarian cancer risk (table 4).


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TABLE 4. Odds ratios* and 95% confidence intervals of ovarian cancer for body mass index at two life periods and body mass index change, Israel, 1994–1999
 
We then performed a conditional multivariate logistic analysis adjusting the association of body mass index at age 18 years for the confounding risk factors shown in table 2. As can be observed in table 5, the association of body mass index at age 18 years persists after adjusting for all confounders (odds ratio = 1.54 for the highest vs. the lowest quartile of body mass index, 95 percent confidence interval: 1.17, 2.02). We repeated these analyses excluding cases diagnosed as borderline ovarian cancer and found similar results.


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TABLE 5. Risk factors associated with epithelial ovarian cancer, multivariate conditional logistic analysis, Israel, 1994–1999
 
We also investigated whether body mass index at age 18 years or during adult life was different among BRCA carriers and noncarriers (cases only) and found no difference between the groups (data not shown).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Our findings demonstrate a statistically significant association between increased body mass index at age 18 years and during "most of adult life" and ovarian cancer risk. The association with body mass index at age 18 years persists after adjusting for change in body mass index from age 18 years to "most of adult life," while the change itself is not significantly associated with ovarian cancer risk. Earlier in this paper we hypothesized that increased body mass index would lead to increased androgenic secretion of ovarian and extraovarian estrogen, but we did not discuss the details of the possible mechanism. One possible mechanism is as follows. It is known that adipocytes secrete leptin (20, 31), and there is strong evidence that leptin stimulates the hypothalamus to produce luteinizing hormone-releasing hormone, which, in its turn, controls (via the pituitary gland) the production of luteinizing hormone and follicle-stimulating hormone, and thereby ovarian function, including secretion of estrogens (19, 20, 27, 3134).

There are several methodological limitations to our study. Participants were not weighed or measured, and true weights could be under- or overstated. Most results of methodological research evaluating the validity of reported compared with measured weight and height show that they are highly correlated and that the reported values are reliable (3539). Troy et al. (39) studied the validity of recalled weight and height by checking recalled weight and height at age 18 years against records of physical examinations conducted at college, and they found the retrospective reports highly valid. In Israel, the body mass index reported by controls in a previous study of breast cancer, using the same set of questions (14), was found to be similarly distributed to the body mass index reported by controls in the present study. At age 18 years, the mean body mass index in the breast cancer study was 21.7 (standard deviation, 3.5) for surgical controls and 21.4 (standard deviation, 3.8) for neighborhood controls, very similar to the present study values of 21.2 (standard deviation, 3.0) among controls.

The response rate of controls in our study was relatively low (67.2 percent). However, we found that two relevant demographic factors, age and place of origin, of those who responded compared with those who did not were similarly distributed, indicating that, at least regarding these proxy variables, no appreciable bias occurred.

The strengths of our study are twofold: 1) it includes a nationwide sample based on the Israeli population and 2) its large size (3,380 individuals). The study includes 76 percent of the total incident cases of ovarian cancer diagnosed during 1994–1999 in Israel.

The role of women’s anthropomorphic characteristics in adulthood and ovarian cancer risk has been studied in only a small number of studies. In the Australian Ovarian Cancer Case-Control Study, based on 1,600 subjects, women with a high body mass index were found to have a statistically significant increased ovarian cancer risk (8). In Japan, various small population studies found a positive association between body mass index and hormone-related women’s cancers, including that of the ovary (10, 12). A positive association between increased body mass index after age 20 years and ovarian cancer risk was found in one of them (12). A prospective study evaluating the association between epithelial ovarian cancer and body fat distribution found that the multivariate-adjusted relative risks for the upper three quartiles of waist/hip ratio compared with the lowest quartile were 2.0, 1.6, and 2.3, respectively (40).

A prospective study in Sweden following a cohort of 47,003 women examined for weight and height in 1963–1965 did not find a significant association between cancer of the ovary and the Quetelet index (11). To our knowledge, the association between body mass index at puberty or age 18 years and ovarian cancer risk has not been evaluated previously in epidemiologic studies, although, as mentioned earlier, Barker et al. (28) showed an increased mortality from ovarian cancer among women who had a high rate of weight gain in infancy.

The question if risk factors behave differently among ovarian cancer BRCA carriers as compared with noncarriers is today a controversial issue that has raised a lot of interest in the last few years. We found no differences in body mass index distribution among BRCA carriers compared with noncarrier ovarian cancer patients and therefore no evidence for an interaction between body mass index and BRCA mutations.

We conclude that, in our population, body mass index at age 18 years is an independent etiologic risk factor for ovarian cancer. The association between ovarian cancer and body mass index during "most of adult life" appears to reflect its association with body mass index at age 18 years.


    ACKNOWLEDGMENTS
 
Supported in part by a research grant from the National Cancer Institute, Bethesda, Maryland (R01-CA61126-01-03), and by contracts with Westat, Rockville, Maryland (NO2-CP-60534 and NO2-CP-91026), and Information Management Services, Silver Spring, Maryland (MS NO2-CP-81005).

The authors are indebted to J. P. Strewing for genetic laboratory work. They also thank L. Shamir and S. Glickman for coordinating the field study work, G. Hirsh-Yechezkel, Ph.D. student, for her contribution to the genetic aspects of the study, T. Rodkin for data entry and programming, and L. Goodman for technical assistance.

They also recognize all the members of the National Israeli Study of Ovarian Cancer: Dr. Marco Altaras, Dr. Shmuel Anderman, Dr. Shaul Anteby, Dr. Jack Atad, Dr. Amiram Avni, Dr. Amiran Bar-Am, Dr. Dan Beck, Dr. Uzi Beller, Dr. Moshe Ben Ami, Dr. Gilad Ben-Baruch, Dr. Yehuda Ben-David, Dr. Haim Biran, Angela Chetrit, Dr. Ram Dgani, Yehudit Fishler, Dr. Ami Fishman, Dr. Eitan Friedman, Dr. Ruth Gershoni, Dr. Reuvit Halperin, Galit Hirsh-Yechezkel, Dr. David Idelman, Dr. Rafael Katan, Dr. Yuri Kopilovic, Dr. Liat Lerner Geva, Dr. Hanoch Levavi, Dr. Beatriz Lifschiz-Mercer, Dr. Zohar Liviatan, Flora Lubin, Dr. Joseph Menzcer, Dr. Baruch Modan (Chairman), Hedva Nitzan, Dr. Moshe Oettinger, Dr. Tamar Peretz, Dr. Benjamin Piura, Dr. Shulamit Rizel, Dr. David Schneider, Dr. Adi Shani, Dr. Chaim Yaffe, Dr. Ilana Yanai, Dr. Shifra Zohar, and Ahuva Zoltan.


    NOTES
 
Correspondence to F. Lubin, Cancer Epidemiology Unit, Gertner Institute, Sheba Medical Center, Tel Hashomer 52621, Israel (e-mail: floral{at}gertner.health.gov.il). Back


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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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