Breast-Cancer Risk Related to Insulin-Resistance Indicators, Elevated Levels of Sex Hormones, UB Study Shows

BUFFALO, N.Y. -- University of Buffalo researchers have confirmed a significant link between breast-cancer risk and physical characteristics of insulin resistance and higher-than-normal male and female sex hormones in a woman's bloodstream.

The study, lead by Paola Muti, M.D., associate professor of social and preventive medicine, appeared in a recent issue of Cancer Causes and Controls.

It is the first major investigation of the association of these characteristics and risk of breast cancer.

Results showed that women with their body fat centered around the abdomen -- a physical attribute associated with insulin resistance -- and women with oily skin and excess body hair (hirsutism) -- signs of higher-than-normal male sexual hormones in the bloodstream -- were at greater risk of developing breast cancer than women without those attributes.

The findings indicated also that the associations differed in pre- and post-menopausal women. Premenopausal women with the highest waist-to-hip ratio (a measure of abdominal fat tissue called abdominal adiposity) were twice as likely to have developed breast cancer than controls, but there was no relationship with sebum production or hirsutism. After adjusting for body mass index, a measure of obesity, the breast-cancer risk related to abdominal adiposity was confined to thinner women, researchers found.

Among postmenopausal women, sebum production and hirsutism, but not abdominal adiposity, were associated with an increased risk of breast cancer. Those with the highest levels of sebum and body hair were at twice the risk, compared to controls.

"These results tell us that our model for describing how insulin induces increased production of androgens and estrogens as precursors to breast cancer is more complex that we thought," Muti said. "There are factors that make insulin a relevant risk factor for younger women, and factors that make androgen and estrogen important risk factors for older women. Now we are trying to find out why this is so."

Insulin resistance and elevated levels of androgens often coexist in women, Muti said, because excess insulin in the bloodstream prompts the ovaries to secrete excess testosterone and estrogen. Higher levels of steroid hormones, in turn, result in excess body hair and increased output of oil and wax (sebum) from sebaceous glands.

This study and earlier research conducted by Muti are based on data from an ongoing prospective study of breast-cancer risk in Northern Italy called ORDET -- HORmone and Diet ETiology of Breast Cancer, which involved 10,786 women. Muti was co-principal investigator for the study.

Women between the ages of 35 and 69 were recruited into the study between 1987 and 1992 and have been followed since. The current findings are based on data collected an average of 5.5 years after the study's inception.

Muti was interested in assessing these physical markers and their association with breast-cancer risk. A more centralized body-fat distribution, reflected by the ratio of waist-to-hip measurement, is considered an indicator of insulin resistance, Muti said.

In persons with insulin resistance, cells do not respond to the role of insulin in promoting passage of glucose and other essential molecules across cell membranes. This resistance results in a buildup of glucose and insulin in the blood stream, and can lead to full-blown diabetes.

Researchers took waist and hip measurements of all participants when they enrolled in the ORDET study. They also evaluated the amount of body hair at nine areas and assessed the amount of sebum production. At 5.5 years after the study began, the ORDET file was linked with local cancer registries, which showed 144 cases of cancer among the study participants.

Comparing these cases with data on the physical indicators of insulin resistance and excess steroid hormones produced the associations with breast cancer and the different effects depending on age.

Additional researchers on the study were Andrea Micheli, Ph.D., Vittorio Krogh, M.D., and Franco Berrino, M.D., from the Instituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy; Martin Stanulla, M.D., from the Medical School of Hannover, Germany; and Jo L. Freudenheim, Ph.D., Jun Yang, M.D., Holger Schunemann, M.D., and Maurizio Trevisan, M.D., from the University at Buffalo. The study was funded by the U.S. Army Medical Research and Material Command.