For a hypothetical cohort of 10,000 women undergoing hysterectomy who chose oophorectomy between the ages of 50 and 54 without estrogen therapy, our analyses predict that, by the time they reach age 80, 838 more women will have died from CHD than in a similar cohort of women who chose ovarian preservation; 158 more will have died from hip fracture; 47 fewer women will have died from ovarian cancer. In the base case analyses, oophorectomy in women ages 50–54 leads to an overall excess mortality of 858 per 10,000 women subjected to surgery.
The increased risk of CHD after oophorectomy was varied, based on estimates from the literature, from 2.2 to no increased risk, showing that the model was very sensitive to changes in the relative risk of CHD, with the probability of death by 80 changing from 46% in the base case (relative risk = 2.2) to about 39% in the extreme case (relative risk = 1) (Table 3). Using the extreme assumption of no deleterious effect of oophorectomy on CHD, for women who had oophorectomy at ages 50–54, the risk of dying by age 80 approached the estimate for ovarian conservation (38.74% and 37.54%). Varying the relative risk of hip fracture mortality between 1 and 2 showed that the model was only slightly sensitive to this measure (Table 3). Based on reported literature, the relative risk of ovarian cancer after ovarian conservation compared with the general population varied between 0.5 and 0.78, and the model was insensitive to this change (results not shown). No sensitivity analyses showed that oophorectomy improved survival.
We designed the model to study the major risks and benefits related to the decision to have prophylactic bilateral oophorectomy when hysterectomy is performed for benign disease in women who have average risk of ovarian cancer. The model shows that women younger than 65 years of age clearly benefit from ovarian conservation, and at no age is there clear benefit from oophorectomy. For women younger than 65 at the time of surgery, oophorectomy increases the risk of dying from coronary heart disease. After age 65, increased mortality is primarily from hip fracture. Because ovarian cancer is a relatively uncommon cause of death when one excludes patients with documented germ-line mutations and pedigrees with high risk for ovarian cancer, our data show no substantial reduction in mortality if oophorectomy is performed before age 65.
For women choosing ovarian conservation at ages 50–54, there is an 8.58% survival advantage measured at age 80, and with surgery at ages 55–59, the survival advantage is 3.92% (results not shown). After age 65, definite conclusions are more difficult to reach. However, at no age does the model suggest a higher mortality for women who chose ovarian preservation because the relative risk of dying from ovarian cancer is overshadowed by the risks from cardiovascular disease and hip fracture.
Hysterectomy alone reduces the risk of ovarian cancer, and the protective effect persists for 10–20 years, long after that expected from screening bias. Interruption of the reproductive tract may be responsible for the decreased risk, because tubal ligation also has a protective effect.3 Heavy menstrual bleeding is associated with a higher risk of ovarian cancer, suggesting that endometrial tissue reflux via the tubes may be the inciting agent. Potential carcinogens, including talc and human papillomavirus, have been found within ovarian cancer tissue.31,32 Epidemiologic studies show decreased ovarian function lowers the risk of developing breast cancer. Women with oophorectomy before age 50 had a 50% decreased risk of breast cancer, which persisted for 10 years after surgery.28
Premenopausal oophorectomy causes an immediate and significant loss of ovarian hormones. Postmenopausal ovaries continue to make small amounts of estrogen for years, and significant levels of ovarian testosterone and androstenedione have been documented in the eighth decade.33 Androstenedione is converted to estrone in fat and muscle, and estrone and testosterone are converted to estradiol. After oophorectomy, menopausal women have significantly lower plasma levels of testosterone than naturally menopausal women.34
Oophorectomy increases the risk of cardiovascular disease, the major cause of death for women. The Nurses' Health Study, a well-conducted prospective study of 121,700 women, determined that oophorectomy between ages 40 and 44 years doubled the risk of myocardial infarction compared with women with intact ovaries.23 Later analysis of the same cohort confirmed these findings.21 These 2 nurses studies report the largest cohort, with the longest-term follow-up, available for CHD data. Earlier age of surgical or natural menopause has been shown to correlate with the risk of cardiovascular mortality.25 Oophorectomy after age 50 increased risk of developing a first myocardial infarction by 40% (relative risk 1.4, 95% confidence interval 1.0–2.0) compared with controls.22 Indirect evidence supports this increased risk. Analysis of data derived from the Women's Health Initiative found that hysterectomy with oophorectomy is an independent predictor of Framingham risk of myocardial infarction or coronary death.35 After oophorectomy, women have higher levels of atherogenic lipids and stress-induced lipids and higher stress-induced systolic and diastolic blood pressures.36 Increased coronary atherosclerosis is found at autopsy in women with prior bilateral oophorectomy.37 Earlier menopause, either natural or surgical, is associated with more subclinical atherosclerosis, as measured by carotid artery intima-media thickness, and this finding is related to the risk of clinical cardiac events.38,39 The Women's Health Initiative found that estrogen therapy did not affect the rate of CHD, suggesting that retention of ovaries and endogenous estrogen may be the best strategy for decreasing the risk of CHD.26
Estrogens and androgens inhibit bone resorption and androgens increase bone formation. Levels of testosterone and estradiol correlate with hip fractures in postmenopausal women.40,41 After a median follow-up of 15 years, women who were postmenopausal at the time of oophorectomy had 54% more osteoporotic fractures than women with intact ovaries.27 Hip fracture is a well-documented cause of increased mortality in older women. A prospective cohort study found that women older than 60 had a 2-fold increase in mortality (odds ratio 2.18, 95% confidence interval 2.03–2.32) after low-trauma hip fractures.17 Women who suffered a hip fracture between ages 60 and 64 were found to have lost 11 years of life, and women with fractures between ages 70 and 74 lost 4.4 years.42
Although quality of life issues are of great importance, insufficient data were available to include these in the decision analysis model. Premenopausal oophorectomy leads to the sudden onset of hot flushes and mood disturbances if estrogen is not taken. Other problems may include a decline in a sense of well-being, a decline in cognitive functioning, poor sleep quality, depression, and a decline in sexual desire and frequency.43 Additionally, a study of functional status found that, before hip fracture, 28% of patients were housebound, but one year later 46% were housebound.17
Although estrogen therapy may reduce some of this risk, one study of 169,000 women enrolled in health maintenance organizations found that, after publication of the Women's Health Initiative results, use of estrogen therapy declined from 12.6% to 9%.44 A previous decision analysis found that, when actual hormone-taking behavior was considered, women who had ovarian conservation had a survival advantage.45
Our study has several weaknesses. The probability estimates were derived mostly from case-control studies, with the inherent weaknesses of selection bias, reporting bias, and chance. One study of coronary heart disease used in our model did not provide information regarding subjects' use of estrogen therapy and may be biased.25 However, our model does not rely on the use of estrogen after oophorectomy. In fact, if estrogen therapy does not reduce CHD mortality, this makes a stronger case for ovarian conservation. No published data were found for coronary risk when oophorectomy is performed after menopause. Further research is needed in this area. Women chosen for most selected studies were predominantly white, and further study is needed to confirm these estimates for nonwhite women. Notwithstanding these limitations, because of the long interval between natural menopause or oophorectomy and the subsequent development of osteoporosis, CHD, breast cancer, or ovarian cancer, it is unlikely that these outcomes will ever be studied in a large, prospective, randomized fashion.
This study was designed to aid women and their doctors in the choice between ovarian conservation and oophorectomy when hysterectomy is performed for benign disease. The risk of developing ovarian cancer becomes substantially lower after hysterectomy, and this risk is overshadowed by increased mortality from CHD and hip fracture for women under the age of 65 when oophorectomy is per formed. We did not demonstrate a survival benefit after oophorectomy at any age because the risks and benefits approximate each other after age 65. Our model suggests that the decision to perform prophylactic oophorectomy should be approached with great caution for the majority of women who are under the age of 65 and who are at average risk of developing ovarian cancer.
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