Key Points Menopausal hormone use (sometimes referred to as hormone replacement therapy or postmenopausal hormone use) involves taking estrogen alone or estrogen in combination with progesterone or progestin, a synthetic hormone with effects similar to those of progesterone (Question 1). In a recent study published in the Journal of the National Cancer Institute, NCI and AARP reported that five or more years of estrogen plus progestin use significantly increased the risk of ovarian cancer for women who have not had a hysterectomy (Question 2).

1. What is menopausal hormone therapy?
Doctors may prescribe hormone therapy in order to alleviate symptoms associated with menopause, such as hot flashes, night sweats, sleeplessness, and vaginal dryness that occur as the body adjusts to decreased levels of estrogen. Menopausal hormone therapy (sometimes referred to as hormone replacement therapy or postmenopausal hormone use) usually involves treatment with either estrogen alone or a combination of estrogen with progesterone or progestin, a synthetic hormone with effects similar to those of progesterone. These two hormones are involved in regulating a woman's menstrual cycle.

Estrogen therapy alone is usually prescribed only for women who have had a hysterectomy. Progestin prevents the overgrowth of cells in the lining of the uterus, which can lead to uterine cancer. Therefore, a combination of estrogen plus progestin is typically recommended for women who have not had a hysterectomy (i.e., women with intact uteri). Hormones may be taken daily (continuous therapy) or on only certain days of the month (sequential therapy).

Before taking hormone replacement products, the U.S. Food and Drug Administration (FDA) currently recommends that women understand the risks and benefits of hormone therapy and talk to their doctors to make appropriate health care choices.

2. Have there been studies of menopausal hormones and ovarian cancer?
Several observational studies have investigated whether women who use menopausal hormones are more or less likely to develop ovarian cancer than women who do not use menopausal hormones. For some diseases, such as breast cancer and coronary heart disease, there are many studies that provide useful data. However, for rare diseases like ovarian cancer, there are fewer studies with the specific data needed to evaluate the potential association between use of menopausal hormones and ovarian cancer.

In a 2006 study, called the NCI Study of Hormone Therapy and Ovarian Cancer, NCI scientists had the opportunity to examine data from a large study that included 23,722 women who had hysterectomies and 73,483 women with intact uteri, to learn whether menopausal hormone use had an affect on risk of ovarian cancer (1).

3. What did the NCI Study of Hormone Therapy and Ovarian Cancer reveal about combination hormone therapy and ovarian cancer?
Overall, in this large study, the risk of developing ovarian cancer was higher in women who used menopausal hormone therapy than in women who never used such therapy. However, the increased risks differed by hormone therapy formulation and regimen and varied according to hysterectomy status.

The following results of the NCI Study of Hormone Therapy and Ovarian Cancer were reported in the October 4, 2006, issue of the Journal of the National Cancer Institute (1).

• Among women with hysterectomy, use of estrogen alone for fewer than 10 years was not associated with ovarian cancer.
• Among women with hysterectomy, use of estrogen alone for 10 or more years was associated with an increased risk of developing ovarian cancer.
• Among women with intact uteri, five or more years of sequential use of estrogen plus progestin (progestin for less than 15 days per cycle) was positively associated with ovarian cancer.
• Among women with intact uteri, five or more years of continuous use of estrogen plus progestin (progestin for 15 days or more per cycle) was positively associated with ovarian cancer, although the observation was not statistically significant.

4. What have previous studies shown about estrogen therapy and the risk of ovarian cancer?
Over the past decade, several studies have reported that long-term use of estrogen increases the risk of ovarian cancer (2-9). One study, conducted at NCI, followed 44,241 menopausal women who had hysterectomies approximately 20 years prior to the start of the study and concluded that women who used estrogen alone for 10 or more years were twice as likely to develop ovarian cancer as women who did not use menopausal hormones (2). Another large observational study also found an association between estrogen use and death due to ovarian cancer. In this study, the increased risk appeared to be limited to women who used estrogen for 10 or more years (9). However, several other studies of women both with uteri (10-13) and without (14,15) found that use of estrogen for hormone therapy does not significantly increase the risk of ovarian cancer.

Since the early 1990s, most women with a uterus are been prescribed a combination therapy of estrogen and progesterone or progestin. Many of the previous studies of estrogen alone included estrogen-only use among women with intact uteri (2-4, 6-8). As a result, the studies that looked at estrogen-only use that only included women with a hysterectomy give a more representative picture of the hormone therapies that are currently used.

5. What have studies shown about the association of estrogen plus progestin combination therapy and the risk of ovarian cancer?
Fewer studies have examined the effect of estrogen plus progestin on the risk of ovarian cancer. The most comprehensive evidence about the risks and benefits of taking combination therapy after menopause comes from the Women's Health Initiative (WHI) Hormone Program, which was sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and NCI, both parts of the NIH. The WHI Hormone Program involved two studies - the use of estrogen plus progestin for women with a uterus (the Estrogen-plus-Progestin study), and the use of estrogen alone for women without a uterus (the Estrogen-Alone study). In both hormone therapy studies, women were randomly assigned to receive either the hormone medication being studied or a placebo.

Data from the WHI Estrogen-plus-Progestin study indicate that there may be an increased risk of ovarian cancer with combined hormone use (16). After 5.6 years of follow-up, a 58 percent increased risk of ovarian cancer was reported in women using estrogen plus progestin compared with nonusers, but the increased risk was not statistically significant.

In comparison, an observational study suggested that combined estrogen-progestin regimens do not increase the risk of ovarian cancer if progestin is used for more than 15 days per month (4), but this study was too small to draw firm conclusions.

Other observational studies have explored estrogen plus progestin and ovarian cancer risk, but some of those studies included women who previously used estrogen alone (8,15) or did not evaluate individual estrogen plus progestin regimens (7,14,15).

6. How was the NCI Study of Hormone Therapy and Ovarian Cancer conducted?
This project was part of a larger NIH-AARP Diet and Health Study. In 1995-1996, the NIH and AARP, the nation's leading organization for persons 50 and older, established the NIH-AARP Diet and Health Study. Two questionnaires were mailed to millions of members to collect information on demographic characteristics, dietary intake, family history of cancer, body mass, physical activity, and use of menopausal hormone therapy. One of the questionnaires collected detailed data on hormone therapy, including whether women had ever used different preparations and formulations. Estrogen or progestin pill users were asked to report dates of first and last use, total duration of use, regimen, usual dose, and the name of the pill that they took for the longest period of time.

The researchers identified participants who developed ovarian cancer during the study follow-up. To do this, they linked the study population to data from the state cancer registries in the eight states where the study participants lived. The NCI investigators then compared history of menopausal hormone therapy use in the women who developed ovarian cancer with the history of menopausal hormone therapy use in the women who did not develop ovarian cancer.

7. What research still needs to be done?
The NCI Study of Hormone Therapy and Ovarian Cancer extends our understanding of ovarian cancer by revealing increased ovarian cancer risks among women with intact uteri who used estrogen plus progestin. Unresolved questions include whether different forms of the hormones, lower doses, different hormones, or different methods of administration are safer or more effective; whether risks and/or benefits persist after women stop taking hormones; whether women might be able to take hormones safely for a short period of time; and whether certain subgroups of women, including women with a history of cancer, might be at higher or lower risk than the general population.

8. Where can people get more information about menopausal hormone use?
The following resources provide additional information about menopausal hormones and the WHI:

• NIH Menopausal Hormone Therapy home page (http://www.nih.gov/PHTindex.htm)
• National Institutes of Health (NIH)-AARP Diet and Health Study (http://dietandhealth.cancer.gov/)
• U.S. Food and Drug Administration Menopause and Hormones Web Information Portal (http://www.fda.gov/womens/menopause/default.htm)
• WHI Participant Web site (http://www.whi.org)
• NCI Menopausal Hormone Use digest page (http://www.cancer.gov/clinicaltrials/digest-postmenopausal-hormone-use)
• NHLBI Postmenopausal Hormone Therapy Web site (http://www.nhlbi.nih.gov/health/women/)
• National Center for Complementary and Alternative Medicine (NCCAM) Menopause Treatments Web page (http://nccam.nih.gov/health/menopause.htm)

Selected References

1. Lacey JV, Brinton LA, Leitzmann MF, Mouw T, Hollenbeck A, Schatzkin A, Hartge P. Menopausal hormone therapy and ovarian cancer risk in the NIH-AARP Diet and Health Study Cohort. Journal of the National Cancer Institute 2006; (98)19: 1397-1405.
2. Lacey JV, Jr., Mink PJ, Lubin JH, Sherman ME, Troisi R, Hartge P, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. Journal of the American Medical Association 2002; 288(3):334-41.
3. Folsom AR, Anderson JP, Ross JA. Estrogen replacement therapy and ovarian cancer. Epidemiology 2004;15(1):100-4.
4. Riman T, Dickman PW, Nilsson S, Correia N, Nordliner H, Magnusson CM, et al. Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. Journal of the National Cancer Institute 2002; 94(7):497-504.
5. Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thun MJ, Heath CW, Jr. Estrogen replacement therapy and fatal ovarian cancer. American Journal of Epidemiology 1995;141(9):828-35.
6. Mills PK, Riordan DG, Cress RD. Epithelial ovarian cancer risk by invasiveness and cell type in the Central Valley of California. Gynecologic Oncology 2004 Oct; 95(1):215-25.
7. Moorman PG, Schildkraut JM, Calingaert B, Halabi S, Berchuck A. Menopausal hormones and risk of ovarian cancer. American Journal of Obstetrics & Gynecology 2005 Jul; 193(1):76-82.
8. Glud E, Kjaer SK, Thomsen BL, Hogdall C, Christensen L, Hogdall E, et al. Hormone therapy and the impact of estrogen intake on the risk of ovarian cancer. Archives of Internal Medicine 2004; 164(20):2253-9.
9. Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. Journal of the American Medical Association 2001; 285(11):1460-1465.
10. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. American Journal of Epidemiology 1992;136(10):1184-203.
11. Kaufman DW, Kelly JP, Welch WR, Rosenberg L, Stolley PD, Warshauer ME, et al. Noncontraceptive estrogen use and epithelial ovarian cancer. American Journal of Epidemiology 1989;130(6):1142-51.
12. Hildreth NG, Kelsey JL, LiVolsi VA, Fischer DB, Holford TR, Mostow ED, et al. An epidemiologic study of epithelial carcinoma of the ovary. American Journal of Epidemiology 1981; 114(3):398-405.
13. Purdie DM, Bain CJ, Siskind V, Russell P, Hacker NF, Ward BG, et al. Hormone replacement therapy and risk of epithelial ovarian cancer. British Journal of Cancer 1999; 81(3):559-63.
14. Sit AS, Modugno F, Weissfeld JL, Berga SL, Ness RB. Hormone replacement therapy formulations and risk of epithelial ovarian carcinoma. Gynecologic Oncology 2002;86(2):118-23.
15. Pike MC, Pearce CL, Peters R, Cozen W, Wan P, Wu AH. Hormonal factors and the risk of invasive ovarian cancer: a population-based case-control study. Fertility and Sterility 2004 Jul;82(1):186-95.
16. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Women's Health Initiative randomized trial. Journal of the American Medical Association 2003; 290(13):1739-1748.

Related Resources

Publications (available at http://www.cancer.gov/publications)

• What You Need To Know About™ Ovarian Cancer

Cancer Information Service (toll-free)
Telephone: 1-800-4-CANCER (1-800-422-6237)/TTY: 1-800-332-8615

Online

• NCI's Web site: http://www.cancer.gov

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