Women with harmful mutations in the BRCA gene, which put them at higher risk of developing breast and ovarian cancer, tend to undergo menopause significantly sooner than other women, allowing them an even briefer reproductive window and possibly a higher risk of infertility, according to a study led by researchers at UC San Francisco.

Moreover, the study showed that carriers of the mutation who are heavy smokers enter menopause at an even earlier age than non-smoking women with the mutation.

While the authors note that further research is needed, given the size and demographics of the study, women with the abnormal gene mutation should consider earlier childbearing, and their doctors should encourage them to initiate fertility counseling along with other medical treatments, the scientists said.

The study will be published online in Cancer on January 29, 2013.

This is the first controlled study to explore the association between BRCA1 and BRCA 2 and the age at onset of menopause, the authors said.

“Our findings show that mutation of these genes has been linked to early menopause, which may lead to a higher incidence of infertility,’’ said senior author Mitchell Rosen, MD, director of the UCSF Fertility Preservation Center and associate professor in the UCSF Department of Obstetrics, Gynecology and Reproductive Sciences. “This can add to the significant psychological implications of being a BRCA1/2 carrier, and will likely have an impact on reproductive decision-making,’’ Rosen said.

Mutations in either of the genes BRCA 1 or BRCA 2 can produce a hereditary, lifetime risk of developing breast cancer and ovarian cancer. Some women decide to reduce their risk by undergoing prophylactic surgery to remove at-risk tissue, including their breasts and ovaries. The abnormal genes are the most identified inherited cause of breast cancer – carriers are five times more likely to develop breast cancer than those without the mutations, according to the National Cancer Institute.

The new study was designed to determine whether women with the BRCA1 or BRCA2 mutation have an earlier onset of menopause compared with unaffected women.

The researchers looked at nearly 400 female carriers of mutations in the BRCA gene in northern California and compared their onset of menopause to that of 765 women in the same geographic area without the mutation. Most of the women in the study were white because almost all of the BRCA1/2 carriers within the UCSF cancer risk registry are white.

The scientists found that women with the harmful mutation experienced menopause at a significantly younger age – 50 years—compared to age 53 for the other midlife women.

Heavy smokers (more than 20 cigarettes a day) with the abnormal gene had an even earlier onset of menopause—46 years. By comparison, only seven percent of white women in northern California had undergone menopause by that age, said the authors. Smoking has been shown to alter menstrual cycles and estrogen status, among other impacts.

The authors point out that while their study shows a possible increased risk of infertility for the mutation carriers, further study is needed. They also said that data regarding the age of natural menopause is limited because most women with the mutation are recommended to undergo risk-reducing surgery after they complete childbearing.

“Women with the mutation are faced with challenges in reproductive choices,’’ said study co-author Lee-may Chen, MD, a professor in the UCSF Department of Obstetrics, Gynecology and Reproductive Services. “These data may help women understand that their childbearing years may be even more limited by earlier menopause, so that they can make decisions about their reproductive choices and cancer risk-reducing surgery.’‘

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The first author of the study is Wayne T. Lin, MD, MPH, who at the time of the research was a resident at UCSF and is now a fellow at the Brigham and Women’s Hospital at Harvard Medical School. Other authors include Marcelle Cedars, MD, a UCSF professor and director of the Division of Reproductive Endocrinology in the Department of Obstetrics, Gynecology and Reproductive Services ; and Mary Beattie, MD, clinical professor in the UCSF Department of Medicine. Study data was collected from the Cancer Risk Program at UCSF and the northern California site of the Study of Women’s Health Across the Nation, a project of the University of California Davis and Kaiser Permanente.

Funding for the study was provided by National Institutes of Health grants NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, and AG012495. Support was also provided by the UCSF Cancer Risk Program Patient Registry, which is supported by the UCSF Helen Diller Family Comprehensive Cancer Center. The Study of Women’s Health Across the Nation has grant support from the NIH, Department of Health and Human Services through the National Institute on Aging, the National Institute of Nursing Research, and the NIH Office of Research on Women’s Health.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

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Elizabeth Fernandez
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University of California - San Francisco