Link Between Ovarian Cancer, BMI May Vary by HRT Use

Nick Mulcahy

January 08, 2009

January 8, 2009 — There is a "modest positive relation" between body mass index (BMI) and risk for ovarian cancer, but the risk is considerably elevated in women who have never used hormone-replacement therapy (HRT), according to a prospective study of 94,000 mostly postmenopausal women published online January 6 in Cancer.

In the study, the risk for ovarian cancer increased by 80% in obese women, compared with normal-weight women, among those who never used HRT.

"Further studies are needed to test the hypothesis that the relation between BMI and ovarian cancer varies according to menopausal hormone therapy," write the authors, led by Michael F. Leitzmann, MD, PhD, from the Institute of Epidemiology and Preventive Medicine at the University of Regensburg, in Germany. Dr. Leitzmann was formerly at the National Cancer Institute in the United States, where the study was undertaken.

In discussing the background of the study, Dr. Leitzmann and colleagues note that "convincing epidemiologic evidence links excess body mass to increased risks of endometrial and postmenopausal breast cancers, but the relation between . . . BMI and ovarian cancer risk remains inconclusive."

The new study adds to the literature on ovarian cancer, BMI, and HRT, which is "sparse," say the authors. They also suspect that any ovarian cancer risk that is associated with obesity is likely related to a "hormonal mechanism."

NIH–AARP Diet and Health Study Used

Using a database from the National Institutes of Health (NIH)–American Association of Retired Persons (AARP) Diet and Health Study (1995–1996), the researchers followed up on an initial mailed health questionnaire from that study with a second questionnaire that inquired about HRT use and family history of cancer. In the end, their analysis included 94,525 women, of whom more than 90% were postmenopausal. State cancer registries were used to identify 303 ovarian cancer cases during follow-up, which lasted until the end of 2003.

At baseline, approximately one third (32.4%) of participants were overweight (BMI, 25–29.9 kg/m2) and nearly one quarter (22.0%) were obese (BMI ≥ 30 kg/m2).


In a multivariate analysis adjusted for factors like age, family history of ovarian cancer, oral contraceptive use, and physical activity, the relative risk (RR) of ovarian cancer for obese women in the cohort was 1.26 (95% confidence interval [CI], 0.94 - 1.68), compared with normal-weight women (BMI, 18.5–24.9 kg/m2).

However, among women who never used HRT, the RR for obese vs normal-weight women was 1.83 (95% CI, 1.18 - 2.84). This association was termed "positive" by the investigators, who also noted that the test for interaction between BMI and menopausal hormone therapy was statistically significant (P = .02).

In contrast, no relation between BMI and ovarian cancer was apparent among women who had used HRT when the obese women were compared with the normal-weight women (RR 0.96; 95% CI, 0.65 -1.43).

Exploratory analyses also suggested a "positive association" between BMI and ovarian cancer among women without a family history of ovarian cancer (multivariate RR for obese vs normal-weight women, 1.36; 95% CI, 1.00 - 1.86), but there was no association between BMI and ovarian cancer among women with a positive family history of ovarian cancer (multivariate RR, 0.74; 95% CI, 0.34 - 1.62).

"Ovarian carcinogenesis has a strong hereditary component, a circumstance that may obscure any true association between BMI and ovarian cancer," write the authors about this latter finding.

Sparse, Conflicting Literature

The new study adds to the sparse but conflicting literature on ovarian cancer risk, BMI, and HRT use, say the authors.

One study had similar results to the current study, finding a positive association between BMI and ovarian cancer mortality among women who never used HRT but not among women who had used HRT (Cancer Epidemiol Biomarkers Prev. 2002;11:822-828). This study differed from the current study in a number of ways, including that the fact that it focused on ovarian cancer mortality and not on ovarian cancer incidence.

Another study — a pooled analysis of 12 cohort studies — found no effect modification of the BMI and ovarian cancer relation by HRT use (Cancer Epidemiol Biomarkers Prev. 2008;17:902-912).

Estrogen Effects at Work?

The authors note that a recent meta-analysis showed a 16% increased risk for ovarian cancer in overweight adults and a 30% increased risk in obese adults, compared with normal-weight adults. (The study did not evaluate HRT use.)

With this and other studies like it in hand, researchers have hypothesized that, in postmenopausal women, excess weight and related adiposity increases ovarian cancer risk through the cellular effects of excess estrogens synthesized in adipose tissue by means of aromatization of androgens.

In keeping with this thinking, the relation between adiposity and ovarian cancer should be weaker among HRT users than among nonusers, because users "already exhibit high circulating estrogen levels by means of an exogenous source," say the authors. This type of interaction between adiposity and HRT has been shown previously for various female cancers, including endometrial and breast cancer.

Additional mechanisms might also be in effect, write the authors. Other possible influences include hyperinsulinemia-related insulin-like growth factor (IGF)-1 and androgens. Both IGF-1 and androgens stimulate cell proliferation in ovarian cancer, they note.

The researchers have disclosed no relevant financial relationships.

Cancer. Published online before print January 6, 2009. Abstract


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