Obesity and Breast Disease

The Role of the Female Sex Hormones

DAVID INGRAM, MB, BS, MS, FRACS, ELIZABETH NOTTAGE, BSC, SIOBHAN NG, LOUISE SPARROW, ANTHONY ROBERTS, MRCPATH, AND DAVID WILLCOX, MSC, DPHlL

An Australian study of 513 women evaluated associations between obesity and both benign and malignant breast disease, and in particular investigated the role of female sex hormones. Women who gained more than 10 kg from early womanhood had a two-fold increase in risk of developing breast cancer, whereas lean women had a greater risk of being treated for benign breast disease. Obese women with breast cancer were more likely to have Stage I1 tumors but there was no significant association between obesity and tumor size or estrogen and progesterone receptor status. Obesity was strongly associated with the pro- portions of nonprotein-bound and albumin-bound estradiol, and inversely associated with sex hormone binding globulin (SHBG) levels and the proportion of SHBG-bound estradiol. In addition, age at menarche was inversely associated, and age at menopause directly associated with recalled weight at those time periods. These data demonstrate weight gain as a risk factor for breast cancer, and suggest a possible mechanism supporting its development.

Cancer 64:1049-1053, 1989.

BESITY IS COMMON in affluent Western societies. 0 Obese women with a body mass index (BMI = weight in kg divided by height in meters, squared) in the range 25 to 30 have an excess mortality of 10% pre- dominantly through the association of obesity with hy- perlipidemia, hypertension, and diabetes mellitus. ' The association of obesity with breast disease is less well rec- ognized. There is some evidence that body size may be a risk factor for the development of breast cance3 and there is quite good evidence that women who have breast cancer and who are obese are more likely to develop metastases and have a shorter survival than nonobese ~ o m e n . ~ - ~

From the University Department of Surgery, Queen Elizabeth I1 Medical Centre, Perth, Western Australia.

Supported by the Cancer Foundation of Western Australia, the Sir Charles Gairdner Hospital Research Foundation, and the Zonta Club of WA.

The authors thank the Cancer Foundation of Westem Australia, the Sir Charles Gairdner Hospital Research Foundation, and the various Western Australian women's support groups for their financial assistance with this project. The authors also thank Mr. Frank Watson of the De- partment of Clinical Biochemistry for assistance with assays, Dr. Dallas English for guidance with statistical methods, Mrs. Peta Diffen for help with collating the data, Professor Roland Hahnel for providing the re- ceptor status data, the Western Australian surgeons who kindly allowed their patients to be studied, and the women who unselfishly gave up their time to participate in the study.

Address for reprints: David M. Ingram, FRACS, Senior Lecturer in Surgery, University Department of Surgery, Queen Elizabeth 11 Medical Centre, Nedlands 6009 Western Australia.

Accepted for publication March 7, 1989.

The relationship of breast cancer to the female sex hor- mones has been more clearly defined in recent years. In particular patients with breast cancer, and those who will go on to develop breast cancer, have higher levels of non- protein-bound estradiol and albumin-bound estradiol and lower levels of sex hormone binding globulin (SHBG)- bound estradiol than Obese women are more likely to have menstrual disturbances and have been shown to have elevated levels of nonprotein-bound and total estrogens,' ' - I 3 thus providing a possible mechanism by which obesity may influence the development of breast disease.

In this study of over 500 women the relationship of obesity to both benign and malignant breast disease was explored, as was the relationship between obesity and the female sex hormones.

Methods

Between February 1985 and August 1987,302 patients with breast cancer and benign breast disease were iden- tified from Pathology Department (Queen Elizabeth I1 Medical Centre, Perth, Western Australia) records and after gaining approval from their surgeon the patients were asked to take part in this survey. The patients were con- tacted 3 to 6 months after their operations and were in- terviewed in their home by a single interviewer (E.M.N.). The source of patients was predominantly a large central teaching hospital (Sir Charles Gairdner Hospital, Perth)

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1050 CANCER September I 1989 Vol. 64

TABLE 1 . Mean f SEM for Variables of Body Size for Each Study Group, Cases, and Controls

Cancer Epithelial hyperplasia Fibrocystic disease

Variable Cases Controls Cases Controls Cases Controls

Weight (kg)* Age 15 Age 25 Age 35 5 years ago

Current weight (kg) Current height (cm) Current BMI (kg m-*) Current skinfold (mm)

52.4 * 1.0 53.9 f 0.7 59.4 f 1.3 63.0 ? 1.1 65.4 f 1.2

160.3 ? 0.6 25.5 f 0.5 18.2? 1.1

53.2 f 0.7 55.8 f 0.8 58.8 f 0.9 62.3 f 1.1 65.2 f 1.1

160.0 f 0.5 25.6 f 0.4 17.7 f 0.5

53.1 f 0.8 55.4 f 0.9 57.1 f 1.3 59.0 f 1.0 61.7 f 1.0

162.6 f 0.8 23.4 f 0.4 14.9 f 0.5

53.2 f 0.7 57.3 * 1.0 58.6 f 1.6 62.3 f 1.2 65.9 f 1.3

161.3 f 0.5 25.3 f 0.5 16.4 f 0.5

53.9 k 0.7 57.4 f 0.8 58.6 f 1.4 60.3 f 1.0 63.8 2 1.2

162.7 f 0.4 24.1 f 0.4 16.1 f 1.2

53.3 f 0.7 57.5 f 1.0 58.6 f 1.6 62.5 f 1.2 66.0 f 1.3

161.2 k 0.5 25.4 f 0.5 16.6 f 0.5

* Estimated.

and five government nonteaching hospitals in Perth. A smaller number of patients came from private hospitals. The patients were matched (by a 5-year age group) and by area of residence (in the same electoral district) to a control subject identified in the electoral roll. These women were contacted by an identical letter to the breast disease patients which asked them to take part in a health survey but without specific mention of breast disease.

A wide range of demographic questions and details re- lating to breast disease were recorded but specific to this report each subject was asked to recall her weight during early womanhood i.e., ages 15, 25, and 35 years, and at 5 years before interview to reflect her weight at around the time of development of her breast disease. Each subject had measurements taken for height, weight, and subscap- ular skinfold thickness using the same measuring devices for each subject.

A single fasting morning blood sample was collected (on day 2 1 or 22 of the menstrual cycle for premenopausal women), and the serum was separated and stored at -70°C until assayed in batches. Concentrations of total estradiol, progesterone, prolactin, and SHBG were mea- sured by radioimmunoassay. The nonprotein-bound pro- portion of estradiol was measured by rate dialysis14 and the albumin-bound component by the same method after heat treatment at 60°C for 1 hour.15 The SHBG-bound component was calculated by subtracting the nonprotein- bound and albumin-bound components from 100%. Breast cancer diameter and number of involved lymph nodes were taken from the histopathology report and es- trogen and progesterone receptor levels were measured by a dextran-coated charcoal methodT6 at the King Edward Memorial Hospital for Women, Perth.

All data were entered into a microcomputer and anal- yses undertaken using the program “Epilog” (Epicentre Software, Pasadena, CA). Relative risk was computed by unconditional logistic regression and the correlations by linear regression analysis.

BMI: body mass index.

Results

Study Subjects

Cases were categorized histologically into either invasive breast cancer patients (BCA, 109 cases), those whose sec- tions revealed benign epithelial hyperplasia (BEH, 96 cases), or those with benign fibrocystic disease without evidence of hyperplasia (FCD, 96 cases). Two hundred eleven community controls were matched by age (5-year intervals) and by area of residence (electoral district) such that each case had one or more controls. For the benign breast group, each patient with BEH was matched to one with FCD and they shared a community control. Ninety- five percent of breast cancer patients, 78% of benign breast disease patients, and 78% of controls contacted agreed to take part in the study.

Obesity and Breast Diseuse

Measures of obesity in cases and controls are shown in Tables 1 and 2. There were no significant differences be- tween breast cancer patients and controls in weight at any age, height, body mass index, or skinfold thickness. There was, however, a significantly increased relative risk for women who gained more than 10 kg from their estimated weight at age 15 years until 5 years before interview (RR 2.1, CL 1.1-4.1, P < 0.05). This weight gain occurred predominantly in the 25-year to 35-year time span.

For the patients with benign breast disease the converse applied. Patients in the BEH group with a body mass index of 20 or less and a skinfold thickness 12 mm or less had a four-fold greater risk of having a biopsy for benign breast disease compared to those with a BMI of greater than 26 or skinfold thickness more than 18 mm. Patients with fibrocystic disease showed a similar but not so marked trend.

No. 5 OBESITY, BREAST DISEASE AND SEX HORMONES * Ingram et al. 1051

TABLE 2. RR, 95% CL, and Significance Values for Selected Variables of Body Size for Each Study Group

Benign epithelial Cancer hyperplasia Fibrocystic disease

Variable Quartiles RR 95% CL RR 95% CL RR 95% CL

Body mass index (compared with BMI of 20 or less)

P-value Skinfold thickness

(compared with skinfold of 12 mm or less)

P-value Weight gain

P-value

21-23 1.27 0.60-2.67 24-26 1.14 0.49-2.62 >26 1.36 0.59-3.27

0.8943

13-15 mm 1.16 0.48-2.8 1 16-18 mm 1.77 0.70-4.46

> I 8 mm 1.77 0.75-4. I5 0.4249

0.02 17 >10 kg 2.1 1 1.10-4.07

0.60 0.19-1.79 0.30 0.09-1.00 0.27 0.09-0.86

0.0380

0.89 0.36-2.19 1.05 0.37-3.04 0.25 0.08-0.72

0.0 126

0.8793 0.95 0.53-1.73

1.05 0.43-2.58 0.71 0.30- 1.69 0.63 0.30-1.31

0.4359

0.80 0.31-2.08 0.91 0.31-2.67

0.17-1.14 0.44 0.2905

0.78 0.42-1.45 0.43

RR: relative risk; CL: confidence limits; BMI: body mass index.

Obesity and Female Sex Hormones

The BMI was correlated against each of the hormonal variables, separately for both the premenopausal and postmenopausal women by linear regression. In pre- menopausal women the BMI was not significantly asso- ciated with total estradiol levels, but did significantly correlate with the proportion of nonprotein-bound (free) estradiol (direct association), the proportion of albumin- bound estradiol (direct association), the proportion of SHBG-bound estradiol (inverse association), and the total SHBG level (inverse association). Progesterone was in- versely associated with BMI but there was no association between BMI and prolactin. For postmenopausal women the associations were the same except for progesterone for which the association no longer held (Table 3). The BMI is plotted against total SHBG and bioavailable estradiol (nonprotein bound plus albumin bound) in Figure 1.

Obesity, Menarche, and Menopause When the woman’s recalled estimate of her weight at

age 15 was correlated against her recalled age at menarche,

there was a significant association: the greater the weight, the earlier the age of menarche (r = -0.166, P < 0.0005). The measured indices of obesity for those women within 10 years of menopause were correlated against age at menopause. There was a significant direct association with both BMI and skinfold thickness: the higher the BMI and the greater the skinfold thickness, the later the age at menopause (BMI, r = 0.188, P < 0.05; skinfold thickness, r = 0.290, P < 0.005).

Obesity and Breast Cancer Prognostic Variables

Both BMI and skinfold thickness were correlated with tumor diameter, the number of involved lymph nodes, and estrogen and progesterone receptor status. Skinfold thickness related to whether lymph nodes were involved or not, patients whose skinfold measurement was greater than 18 mm being significantly more likely to have in- volved nodes with tumor ( P = 0.040, Fisher’s exact test two-sided). Although there was a trend towards these pa- tients having bigger tumors this was not significant. Body mass index did not relate to either tumor diameter or number of involved lymph nodes. Neither index of obesity

TABLE 3. Correlation of BMI Against Each Hormonal Variable for Premenopausal and Postmenopausal Groups: Cases and Controls

Variable

Premenopausal women Postmenopausal women

Correlation Correlation coefficient Significant coefficient Significant

(r) (0 (r) (PI ~~ ~~

Total oestradiol -0.079 NS 0.032 NS Nonprotein-bound oestradiol 0.326 <o.ooo 1 0.377 <0.0001 Albumin bound oestradiol 0.313 <0.0001 0.31 1 <o.ooo 1 SHBG bound oestradiol -0.306 <o.ooo I -0.3 13 <o.ooo 1 Total SHBG -0.218 <o.ooo 1 -0.354 <0.0001 Progesterone -0.179 <0.005 -0.092 NS Prolactin -0.049 NS 0.0 I8 NS

BMI: body mass index; NS: not significant: SHBG: sex hormone binding globulin.

1052 CANCER September 1 1989 Vol. 64

90 1 r 90 - 80 - 70 -

60

50 -

40 -

- 80

- 70

- 60

50

40 SEX HORMONE BINDING GLOBULIN * BD-AVAILABLE OESTRADDL

BODY MASS INDEX (kg.rn-’ )

FIG. 1. The SHBG (nM. I-’) levels and the percentage of bioavailable oestradiol (nonprotein-bound plus albumin bound) plotted against Body Mass Index (Wt/Htz) for all women in the study, excluding those taking hormonal preparations.

was related to estrogen or progesterone receptor status, either for premenopausal or postmenopausal women or the group as a whole.

Discussion This study sought associations between obesity and

breast disease, and explored possible mechanisms, partic- ularly hormonal, by which obesity might act on the breast. As regards breast cancer, overall the cases were no more obese than controls. However, the finding that women who gain more than 10 kg have a significantly greater risk for the development of breast cancer is new, and this weight gain occurred predominantly between the years 25 to 35. By comparison, women with benign breast dis- ease were significantly more likely to be less obese and have reduced skinfold thickness than controls. This ob- servation has been made previously and the explanation given is that thin women have small breasts and are there- fore more likely to find a lump and have it removed com- pared to obese women, rather than thin women having a greater incidence of benign breast di~ease.’~,’~

Possible associations between obesity and hormones were sought to explore the hypothesis that obesity influ- enced the development of breast cancer by hormonal stimulation of mammary duct epithelium. Strong asso- ciations were demonstrated. The greater the level of obe- sity the greater the proportion of bioavailable estradiol, i. e., nonprotein-bound and albumin-bound components, and the lower the SHBG binding as well as total levels of SHBG. This applied to both premenopausal and post- menopausal women. Obesity is thought to raise estrogen levels by increasing the conversion of estrone and estradiol from their precursors by aromatase enzymes in the lipo- cytes.13 Recent work has suggested that breast cancer pa- tients have considerably greater aromatose activity in the

adipose tissue adjacent to the tumor,I9 suggesting that the local hormone environment is important in breast cancer development.

Progesterone was inversely associated with obesity in premenopausal women suggesting a possible imbalance of the estrogen-to-progesterone ratio and hence another mechanism for possible breast cancer development, the so-called “estrogen window hypothesis.”” We found no association between prolactin and indices of obesity and although this finding is similar to most previous studies, one report demonstrated higher evening prolactin levels in obese postmenopausal women.21 The relationship be- tween obesity and hormones and breast cancer was also manifest, somewhat indirectly, by the findings that in- creased weight was associated with an early age at men- arche and with a late age at menopause, both well-rec- ognized risk factors for breast cancer.22323

It is known that obesity is an important prognostic in- dicator in breast cancer pat ient~.~-~ Obese women with breast cancer are more likely to develop metastases and survive a shorter time than their nonobese counterparts. In this study we investigated the association between obe- sity and a number of prognostic variables: breast cancer tumor diameter, number of involved lymph nodes, and estrogen and progesterone receptor status. Obese women were more likely to have Stage I1 tumors, i.e., involved lymph nodes, than nonobese women. Whether the tumors are more advanced on account of a hormonal milieu more favorable to growth, or whether there is a simple physical explanation such that the converse of women with benign breast disease applies, i.e., obese women have large breasts and therefore have difficulty in detecting their tumor until it is at a more advanced stage compared to nonobese women, is unknown.24 The absence of any association between obesity and receptor status of breast cancer in this study differs from de Waard’s study.’

In conclusion, it is apparent weight gain increases the risk of a woman developing breast cancer and may result in her having a more advanced tumor at time of diagnosis. Obese women have higher levels of bioavailable estradiol and a lower progesterone level (in premenopausal women) and this alteration in hormonal environment is put for- ward as a possible explanation for the increase in risk. We are currently undertaking a study to determine if weight loss alters estrogen binding. As regards preventing breast cancer, avoiding obesity is a potential measure to reduce the morbidity and mortality of this all too common disease.

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