http://www.medscape.com/viewarticle/544956_print
News Author: Caroline Cassels
CME Author: Charles Vega, MD, FAAFP
Release Date: September 22, 2006;
Valid for credit through September 22, 2007
Credits Available
Physicians - maximum of 0.25
AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians
All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.
Physicians should only claim credit commensurate with the extent of their participation in the activity.
September 22, 2006 — Women younger than 45 years who undergo prophylactic bilateral oophorectomy and do not receive adequate estrogen replacement therapy have a 70% higher mortality risk, a study reports.
The Mayo Clinic Cohort Study of Oophorectomy and Aging, a large, long-term observational study of 4780 subjects, found young women who undergo surgical removal of both ovaries and do not receive long-term estrogen replacement therapy have a 1.7 times greater all-cause mortality risk.
"We were struck by the fact that instead of benefiting from the procedure, women age 45 or younger who undergo oophorectomy for the prevention of ovarian cancer are at a distinct long-term disadvantage as shown by a 70% increased mortality risk," principal investigator Walter Rocca, MD, from the Mayo Clinic in Rochester, Minnesota, told Medscape.
The study is published in the September 14 Early Online Publication issue of
The Lancet Oncology.
This finding, said Dr. Rocca, who is a neurologist and epidemiologist, was unexpected. He and his team were looking at the long-term neurologic impact of estrogen deficiency prior to menopause, particularly as it relates to Parkinson's disease and dementia, including Alzheimer's disease.
What came to light was the finding that bilateral oophorectomy in young women was associated with an increased risk for mortality from breast and uterine cancers, as well as cardiovascular and neurologic disease. However, this increased risk was not apparent until an average of 10 years or more postoperatively.
"It was surprising to find that despite removal of the ovaries, which we thought would have a protective effect, by reducing estrogen these young women still had an increased risk of estrogen-related cancer," said Dr. Rocca.
But perhaps even more striking, Dr. Rocca said, was the finding that estrogen deficiency at an early age increases neurologic and cardiovascular mortality, suggesting estrogen has a neuroprotective and cardioprotective effect.
The Big Picture
Dr. Rocca added that the study's 30-year follow-up was invaluable in revealing the mortality risk. "We are talking about events that occur up to 30 years after surgery, so physicians performing oophorectomies, who may typically follow their patients for a few years post-operatively, aren't able to see these effects. It is only when you look at this from a historical perspective that you are able to see the big picture," he said.
The cohort study included all women who underwent unilateral or bilateral oophorectomy for noncancer-related indications in Olmsted County, Minnesota, between 1950 and 1987. Each member of the cohort was then age-matched to a subject in a referent group of women in the same population who had not undergone oophorectomy.
Of the eligible participants, there were 1293, 1097, and 2390 women in the unilateral, bilateral, and referent groups, respectively.
Analyses were done for unilateral and bilateral oophorectomy groups by surgical indication and age at surgery. In addition, because most women who underwent a bilateral procedure received estrogen, investigators also stratified patients according to age at surgery plus total duration of subsequent estrogen treatment.
While overall mortality was not increased in women who underwent prophylactic bilateral oophorectomy compared with the referent group, there was a significant increased risk for death from all causes among those who received the procedure before age 45 years and who did not receive estrogen up to the age of 45 years.
In addition, the researchers found no increased mortality risk among women who underwent unilateral oophorectomy, either overall or in the stratified analyses.
Age-Dependent Effect
Based on this study, it is clear, said Dr. Rocca, that estrogen has a beneficial, albeit, age-dependent effect. "Estrogen appears to be extremely important in young women, a little less important in the perimenopausal and early postmenopausal phase of life, and has a possible detrimental effect — as was shown in the Women's Health Initiative (WHI) — in the later stages of life."
Launched in 1991 to determine, among other things, the effect of estrogen on cardiovascular health in postmenopausal women, the WHI was stopped in 2004 after it was found estrogen significantly increased ischemic stroke risk in study participants, who had an average age of 63 years.
Since then, said Dr. Rocca, there has been a tendency by the medical community to interpret estrogen replacement therapy as risky. However, he said, it appears from this study that, in fact, at certain stages of life estrogen is protective.
Bobbie Gostout, MD, a gynecologic surgeon also at the Mayo Clinic, but who was not one of the study authors, also believes there has been a tendency to misinterpret the WHI findings.
"There has definitely been some non-uniform interpretation of the WHI that has resulted in some clinicians overemphasizing the possible detrimental effects of estrogen in their younger patients. Dr. Rocca's study reminds us that we need to look at this younger age group differently and that estrogen has different effects at different phases of life," she said.
Practice Shift Warranted
These findings, said Dr. Rocca, strongly indicate clinicians should revisit the use of prophylactic bilateral oophorectomy in their young patients.
Dr. Gostout agrees and said in light of this study clinicians should carefully reconsider the risks and benefits of removing a woman's ovaries.
"In women at high risk of ovarian or breast cancer I suspect we will still encourage oophorectomy at age 35, or after they've finished their childbearing years. But in lower risk women, I think there will be an increased trend toward conserving the ovaries," Dr. Gostout told Medscape.
Currently, she said, there are approximately 300,000 prophylactic oophorectomies performed in the United States annually. While it is not clear what proportion of these women is younger than 45 years, Dr. Gostout noted that in the study population approximately 25% of subjects were in this age category. This suggests that approximately every year 75,000 women younger than 45 years undergo this procedure.
Both Drs. Rocca and Gostout believe young women who do undergo prophylactic bilateral oophorectomy need to be prepared to take long-term estrogen therapy to reduce their mortality risk.
However, Dr. Rocca noted that in addition to the issue of estrogen replacement therapy compliance, which is typically poor, it is still not clear whether estrogen replacement therapy has an equivalent protective effect as endogenous estrogen. Therefore, he said, at this point, the best option is to preserve the ovaries, if possible.
Lancet Oncol. Published online September 14, 2006.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
- Describe previous research exploring the risk for mortality associated with prophylactic oophorectomy in women with mutations of the BRCA gene.
- Identify the mortality risk associated with unilateral and bilateral oophorectomy.
Clinical Context
Prophylactic oophorectomy may improve outcomes among women with mutations of the
BRCA gene. In a study of 666 women with mutations of the
BRCA gene by Domchek and colleagues, which was published in the March 2006 issue of
The Lancet Oncology, prophylactic oophorectomy was associated with reduced overall mortality in most analyses. However, oophorectomy was effective in reducing the risk for breast- or ovarian-cancer–specific mortality only in some analyses.
The issue of whether prophylactic oophorectomy improves mortality outcomes remains controversial. The current study reexamines this issue in a retrospective cohort analysis.
Study Highlights- The study compared women who did and did not undergo oophorectomy in 1 county in Minnesota. Only women born before 1962 who had an oophorectomy between 1950 and 1987 were included in the study analysis. All subjects had oophorectomy prior to menopause. Women who underwent oophorectomy for ovarian cancer or other estrogen-related cancers were excluded from study analysis.
- The main study outcome was the relationship between unilateral and bilateral oophorectomy and the risk for death. Women with oophorectomy were compared with age-matched controls. Mortality was confirmed through telephone contacts, review of the medical records, and a state mortality database.
- The eligible participants of the study included 1293 women with unilateral oophorectomy, 1097 women with bilateral oophorectomy, and 2390 women in the referent group.
- Among women receiving unilateral oophorectomy, 74% had a benign indication for surgery, while 26% underwent oophorectomy as prophylaxis. The respective percentages for benign and prophylactic surgical indications among women with bilateral oophorectomy were 51% and 49%. The majority of women had a concomitant hysterectomy with oophorectomy.
- The median follow-up period for the study cohort was more than 25 years. Overall, women who underwent bilateral oophorectomy did not have an increased mortality risk compared with the referent group, but women who had oophorectomy prior to age 45 years experienced a mortality hazard ratio of 1.67 vs the referent group. This risk was similar regardless of the indication for surgery, but receiving exogenous estrogen up to age 45 years mitigated against the risk for death among women with oophorectomy at younger ages.
- Unilateral oophorectomy was generally not associated with a significant difference in mortality compared with the referent group. However, unilateral oophorectomy for endometriosis or when combined with hysterectomy conferred a survival benefit.
- Women with bilateral oophorectomy prior to age 45 years had higher rates of mortality due to estrogen-related cancers as well as other nonmalignant causes of death.
Pearls for Practice- A previous study could not confirm the overall mortality or cancer-specific mortality benefit in all analyses of prophylactic oophorectomy for women with mutations of the BRCA gene.
- The current study demonstrates that women who undergo prophylactic bilateral oophorectomy prior to age 45 years are at an increased risk for mortality compared with women who do not have oophorectomy, particularly in cases in which women
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