Progestin may reduce ovarian cancer risk
Family planners are familiar with the fact that combined oral contraceptive (OC) use is associated with a reduced risk for ovarian cancer. New research now indicates that the progestin contained in combined pills may play a dominant role in the chemical prevention of the disease.
Two papers just published in the Journal of the National Cancer Institute examine this relationship. In one study, researchers found that pills containing high levels of progestin are associated with a lower risk of ovarian cancer than oral contraceptives with low progestin content.1 The other study links the progestin component in the Pill to increased cell turnover in the ovarian epithelium, which indicates that the hormone may lower ovarian cancer risk by activating cancer-preventative molecular pathways in the ovary.2
According to Contraceptive Technology, when compared with never-users, women who have used OCs for four years or less are 30% less likely to develop ovarian cancer; for five to 11 years, 60% less likely; and for 12 or more years, 80% less likely.3
"Because there is a large volume of evidence that has linked ovulation with ovarian cancer risk, and because the Pill inhibits ovulation for contraceptive purposes, it was previously assumed that [ovulation inhibition] was the mechanism underlying the protective effect of the Pill against ovarian cancer," says Gus Rodriguez, MD, director of the division of gynecologic cancer at Evanston (IL) Northwestern Healthcare and associate professor in the department of obstetrics/gynecology at Northwestern University Medical School in Chicago.
Rodriguez and colleagues at Duke University Medical Center in Durham focused their initial research on how hormones affect the ovaries of macaque monkeys, whose reproductive biology is similar to that of humans. They found that progestin activates the process of apoptosis in the ovarian lining.4 Apoptosis is a biologic function that eradicates genetically damaged cells prone to malignancy.
The new research indicates that progestin-exposed surface cells also produce higher amounts of a certain protein, called transforming growth factor-beta (TGF-beta), which is associated with several cancer-preventing cellular pathways. Investigators also note that the amount of TGF-beta in the progestin-exposed ovaries correlates well with the percentage of cells undergoing apoptosis.
Does dose matter?
Duke researchers then decided to test the theory that progestin potency may relate to the decreased risk of ovarian cancer observed with oral contraceptive use, says Joellen Schildkraut, PhD, associate professor in the university’s department of community and family medicine.
Schildkraut and colleagues studied 390 women with epithelial ovarian cancer and 2,865 control subjects. The women were between 20-54 years of age and had been identified from a study known as the Cancer and Steroid Hormone study.5 The study, conducted from 1980 to 1982, collected data on ovarian cancer rates and oral contraceptives use in women to examine the protective effect of specific OC formulations on ovarian cancer risk.
In the original study, all of the pill formulations appeared to reduce ovarian cancer risk. The new research reanalyzed the data to determine the impact of the dose levels of estrogen and progestin levels on cancer protection.
The researchers found that OCs with higher levels of progestin are associated with a greater reduction of ovarian cancer risk of than those with a lower progestin dose. Findings also indicate that women who took pills with higher progestin levels showed a significant reduction in risk, even when the pills were taken for a short time.
New formulations eyed
What does this mean? Rodriguez believes the evidence points to a number of molecular pathways that can be exploited for cancer prevention.
Whether the progestin effect is due to apoptosis, TGF-beta, or a combination of the two, scientists now can focus on new formulations, both for women who need contraception and those who are menopausal.
"If it is a biologic effect and not an effect related to ovulation inhibition, then perhaps we can develop an effective preventive that all women can use, including those that are menopausal who don’t ovulate and comprise a group of women at greatest risk for ovarian cancer," says Rodriguez.
References
1. Schildkraut JM, Calingaert B, Marchbanks PA, et al. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst 2002; 94:32-38.
2. Rodriguez GC, Nagarsheth NP, Lee KL, et al. Progestin-induced apoptosis in the macaque ovarian epithelium: Differential regulation of transforming growth factor-beta. J Natl Cancer Inst 2002; 94:50-60.
3. Hatcher RA, Trussell J, Stewart F, et al. Contraceptive Technology. 17th revised ed. New York: Ardent Media; 1998.
4. Rodriguez GC, Walmer DK, Cline M, et al. Effect of progestin on the ovarian epithelium of macaques: Cancer prevention through apoptosis? J Soc Gynecol Investig 1998; 5:271-276.
5. Centers for Disease Control and Prevention. Oral contraceptive use and the risk of ovarian cancer. The Centers for Disease Control Cancer and Steroid Hormone (CASH) study. JAMA 1983; 249:1,596-1,599.
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