Ovarian Cancer Risk in Relation to Estrogen/Progestin Dose and Use Characteristics of Oral Contraceptives

ABSTRACT & COMMENTARY

Synopsis: Use of lower dose oral contraceptives formulations afforded the same protection against ovarian cancer as did higher dose preparations.

Source: Ness RB, et al. Am J Epidemiol 2000;152:233-241.

Oral contraceptive (oc) use has many benefits and some risks. In an effort to maximally minimize risks, the standard doses of ethinyl estradiol have been gradually decreased over the intervening decades. The customary dose now ranges from 20-35 µg daily rather than the 50-80 µg daily dose range used in the past. While this strategy has been associated with a decrement in some risks and nuisance side effects,1 concern has been raised that the newer formulations may not afford the same protection against ovarian and endometrial cancers. The present study was undertaken to determine if the risk reduction for ovarian cancer was comparable with the use of lower dose OC preparations.

Ness and colleagues conducted a population-based, case-control investigation designed to determine the degree of risk reduction of ovarian cancer across generations of women. Cases were women 20-69 years of age who had been diagnosed with epithelial ovarian cancer within the six months prior to interview. There were a total of 767 cases in the final cohort. Controls aged 65 years or younger were ascertained by random digit dialing. Controls aged 65-69 years of age were ascertained through Health Care Financing Administration lists. There were 1367 controls. Standard 1.5-hour interviews were conducted by trained interviewers in the homes of participating women. Detailed demographic and reproductive information was obtained.

The risk of ovarian cancer was reduced approximately 40% for OC users overall, after adjusting for age, gravidity, family history of ovarian cancer, and race. There was no correlation between estrogen and progestin dose and risk reduction. Thus, the lower dose OC preparations yielded comparable odds ratios. Not unexpectedly, pregnancies and live births were associated with a reduced risk of ovarian cancer; most of the effect occurred with the first reproductive event. Compared with white women, those in other racial groups were less likely to have ovarian cancer. Women who breastfed, particularly those who did so longer than 12 months, were somewhat less likely to develop ovarian cancer. Neither age at menarche nor age at menopause was associated with ovarian cancer risk, nor was body mass index. Women who initiated use at or about age 35 years were afforded the same protection. Very long-term use (³ 10 years) was associated with an even greater risk reduction.

COMMENT by Sarah L. Berga, MD

The main mechanism by which OC use is thought to guard against the development of ovarian cancer is suppression of ovulation. Since lower dose preparations are generally as efficacious as higher dose preparations in this regard (when used as directed), it has been predicted that lower dose preparations would afford comparable protection against ovarian cancer. This study has provided the best evidence to date in support of this hypothesis. This is certainly good news. Not only do lower dose preparations have fewer of the nuisance side effects that lead women to discontinue oral contraceptives,2 but they also reduce the risk of serious complications such as venous thromboembolic events.

This study raises again the question as to how low can we go with the steroid doses in oral contraceptives? To my mind, the ideal OC is one that suppresses ovulation reliably, produces amenorrhea, and provides sufficient estrogen for bone accretion, optimal brain function, maintenance of the urogenital tract, and promotion of cardiovascular health. At a recent meeting, it was suggested that the ideal OC should also not suppress or even enhance libido. While safety and contraceptive efficacy remain paramount, we must recognize that quality-of-life parameters gate satisfaction and, therefore, continued use. This study suggests that we should be able to redesign oral contraceptives to yield excellent safety profiles. Now we need to also focus our attention on the design of better instruments that capture the quality-of-life side of this equation, so that we can focus on those aspects and bleeding patterns.

The issue of lowering the estrogen dose may prove even more critical for that subset of women with BRCA mutations. It has been shown that oral contraceptives reduce the risk of ovarian cancer in this high-risk group.3 While OC use does not appear to increase the risk of breast cancer in unselected women, there has been concern that their use may increase the risk of breast cancer in this particular group.4 Therefore, it may well be especially advantageous in this clinical situation to minimize the overall dose. The key to doing so will undoubtedly involve tinkering with both the format and the composition of oral contraceptives. Hopefully, there will be a pharmaceutical house with sufficient interest in this difficult undertaking. 

References

1. Gillum LA, et al. JAMA 2000;284:72-78.

2. Rosenberg MJ, Waugh MS. Am J Obstet Gynecol 1998;179:577-582.

3. Narod SA, et al. N Engl J Med 1998;339:424-428.

4. Ursin G, et al. Cancer Res 1997;57:3678-3681.