To Save or Not to Save the Ovaries: The Mayo Clinic Study

Abstract & Commentary

By Leon Speroff, MD, Editor, Professor Emeritus of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: The Mayo Clinic Cohort Study of Oophorectomy and Aging finds that premenopausal bilateral oophorectomy is followed by a broad spectrum of adverse consequences, all related to estrogen deficiency.

Source: Rivera CM, et al. Increased mortality for neurological and mental diseases following early bilateral oophorectomy. Neuroepidemiology 2009;33:32-40.

The Mayo Clinic Cohort Study of Oophorectomy and Aging included 1274 premenopausal women with unilateral oophorectomy (followed for a median of 29.5 years) and 1091 premenopausal women with bilateral oophorectomy (followed for a median of 25 years) who had surgery from 1950 through 1987, compared with 2383 matched women from the same population of women who had not undergone oophorectomy.1 Women with bilateral oophorectomy before age 45 had about a 5-fold increase in risk of mortality for neurological or mental diseases. Data from this same study also indicated that women with bilateral oophorectomy before age 45 experience almost a 2-fold increase in mortality from cardiovascular disease; an increased risk of parkinsonism, cognitive impairment and dementia; and an increase in depressive and anxiety symptoms later in life.2-5

Commentary

Patients and clinicians often have to decide whether it is worthwhile to perform prophylactic bilateral oophorectomy to prevent ovarian cancer. And if preventive oophorectomy is elected, another question must be addressed: Should estrogen treatment follow surgery, and if so, for how long?

Overall, mortality from all causes was not increased in the Mayo cohort of premenopausal women with bilateral oophorectomy; however, it was significantly higher in those who underwent prophylactic oophorectomy before age 45, mainly in women not treated with estrogen.6 In the analysis of mortality associated with cardiovascular disease, women with bilateral oophorectomy before age 45 treated with estrogen had no increase in mortality. These findings are consistent with the long-recognized increase in cardiovascular disease that follows pre-mature menopause in women not treated with estrogen.7 This was documented even in the coronary artery calcium study nestled within the Women's Health Initiative that demonstrated an increase in subclinical coronary disease in women not treated with estrogen after bilateral oophorectomy.8

The adverse effects in multiple organs of prophylactic bilateral oophorectomy before the age of menopause cannot be disputed. To be sure, there at least two benefits: a reduced risk of ovarian cancer and a reduced risk of breast cancer. With 24 years of follow-up, the Nurses' Health Study compared ovarian conservation (13,035 women) and bilateral oophorectomy (16,345 women) at the time of premenopausal hysterectomy.9 It required bilateral oophorectomy in 220 women to achieve a reduction in breast and ovarian cancer in 1 case. However, total cancer mortality increased, most notably an increase in lung cancer, 1 case after each 190 surgeries. An all-cause increase in mortality, coronary heart disease, and stroke was observed in those women who never used estrogen after surgery; this amounted to 1 additional death for every 9 surgeries.

Many years ago, my brother Ted concluded in his PhD thesis that an adverse impact on health followed elective bilateral oophorectomy, mainly because compliance with estrogen therapy following surgery was not sufficient to overcome the impact of estrogen deficiency after surgery.10 The prophylactic benefit of premenopausal bilateral oophorectomy does not outweigh the increase in mortality and adverse events, unless each patient adheres to a long-term regimen of estrogen therapy.

Does estrogen therapy after surgery negate the beneficial reduction in breast cancer risk associated with bilateral oophorectomy? In a cohort of women with BRCA1/2 who had oophorectomy and a 60% reduction in the risk of developing breast cancer, hormone therapy of any type did not alter the reduction in breast cancer experienced by the women undergoing oophorectomy.11 The average length of follow-up was 2.6 years (more than 5 years in 16%) in the surgically treated group and 4.1 years (more than 5 years in 33%) in the non-oophorectomized group. There was no hint of a difference in breast cancer reduction comparing hormone users and non-users. The findings were similar in 34 women who used a combination of estrogen and progestin, but the power of this finding was limited by the small number.

A case-control study of 472 postmenopausal women with a BRCA1 mutation found that women who used hormone therapy after prophylactic oophorectomy, either estrogen-only or combined estrogen-progestin, not only did not have an increased risk of breast cancer, but hormone use was actually associated with a decreased risk.12 The findings were the same regardless of duration of use or current or past use. The conclusion is encouraging, but limited by the fact that 68% of the tumors in the study were estrogen-receptor-negative, making the estrogen-receptor-positive tumors (that are more likely to be influenced by hormone use) relatively small in number.

Clinical lessons:

  1. Elective bilateral oophorectomy before the age of menopause is recommended only in the presence of specific indications such as BRCA mutations or severe endometriosis.
  2. Women who choose to undergo elective bilateral oophorectomy must be cautioned that long-term adherence to a regimen of estrogen therapy will be required to prevent an increased risk of mortality.
  3. Women who are BRCA carriers face difficult decisions regarding hormonal treatment for menopausal symptoms. Experience thus far indicates that hormone therapy can be used safely for several years. Continued follow-up of these patients may extend this period of safety even longer.

References

  1. Rivera CM, et al. Increased mortality for neurological and mental diseases following early bilateral oophorectomy. Neuroepidemiology 2009;33:32-40.
  2. Rivera CM, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause 2009;16:15-23.
  3. Rocca WA, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology 2008;70:200-209.
  4. Rocca WA, et al. The long-term effects of oophorectomy on cognitive and motor aging are age dependent. Neurodegener Dis 2008;5:257-260.
  5. Rocca WA, et al. Long-term risk of depressive and anxiety symptoms after early bilateral oophorectomy. Menopause 2008;15:1050-1059.
  6. Rocca WA, et al. Survival patterns after oophorectomy in premenopausal women: A population-based cohort study. Lancet Oncol 2006;7:821-828.
  7. Atsma F, et al. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: A meta-analysis. Menopause 2006;13:265-279.
  8. Allison MA, et al. Oophorectomy, hormone therapy, and subclinical coronary artery disease in women with hysterectomy: The Women's Health Initiative coronary artery calcium study. Menopause 2008;15(4 Pt 1):639-647.
  9. Parker WH, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses' Health Study. Obstet Gynecol 2009;113:1027-1037.
  10. Speroff T, et al. A risk-benefit analysis of elective bilateral oophorectomy: Effect of changes in compliance with estrogen therapy on outcome. Am J Obstet Gynecol 1991;164(1 Pt 1):165-174.
  11. Rebbeck TR, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. J Clin Oncol 2005;23:7804-7810.
  12. Eisen A, et al. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 2008;100:1361-1367.