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Abstract

Bilateral oophorectomy at the time of hysterectomy for benign disease is commonly practiced in order to prevent the subsequent development of ovarian cancer or other ovarian pathology that might require additional surgery. At present, bilateral oophorectomy is performed in 78% of women aged between 45 and 64 years having a hysterectomy, and a total of approximately 300,000 prophylactic oophorectomies are performed in the USA every year. Estrogen deficiency resulting from pre- and post-menopausal oophorectomies has been associated with higher risks of coronary heart disease, stroke, hip fracture, Parkinsonism, dementia, cognitive impairment, depression and anxiety in many studies. While ovarian cancer accounts for 14,800 deaths per year in the USA, coronary heart disease accounts for 350,000 deaths per year. In addition, 100,000 cases of dementia may be attributable annually to prior bilateral oophorectomy. At present, observational studies suggest that bilateral oophorectomy may do more harm than good. In women who are not at high risk of developing ovarian or breast cancer, removing the ovaries at the time of hysterectomy should be approached with caution.

Keywords

dementia depression estrogen deficiency heart disease hysterectomy menopause oophorectomy osteoporosis ovarian cancer ovarian conservation ovaries Parkinsonism stroke women's health women's sexuality

Bilateral oophorectomy at the time of hysterectomy for benign disease is commonly practiced in order to prevent the subsequent development of ovarian cancer. Other rationales for oophorectomy include avoiding subsequent ovarian pathology or adnexal pain from postsurgical adhesions that might require additional surgery. Owing to these concerns, 55% of all women and 78% of women between 45 and 64 years of age have bilateral oophorectomy at the time of a hysterectomy [201]. Conservative estimates suggest that approximately 300,000 US women have prophylactic bilateral oophorectomy at the time of hysterectomy every year.

Premenopausal oophorectomy causes a rapid decline in circulating ovarian estrogens and androgens, often leading to hot flashes, sleep disturbance, mood alteration and vaginal dryness with associated painful intercourse. Postmenopausal ovaries continue to produce significant amounts of the androgens testosterone and androstenedione, which are converted to estrogen peripherally [1,2]. These levels are consistently produced and have been documented to the age of 80 years [3]. Pre- and post-menopausal oophorectomies, and the resulting estrogen deficiency, have been associated with higher risks of coronary heart disease (CHD) and hip fracture in some, but not all, studies [4,5]. Recent evidence also suggests an association of oophorectomy with higher risks of Parkinsonism, dementia, cognitive impairment, depression and anxiety [6 –8]. While ovarian cancer accounts for 14,800 deaths per year in the USA, CHD accounts for 350,000 deaths per year and hip fracture may account for approximately 66,000 deaths per year. In addition, dementia is estimated to affect between 1 and 2 million US women, and as many as 10% of these cases may be attributable to prior bilateral oophorectomy [9]. Reoperation for adnexal pathology or adhesions subsequent to hysterectomy is rare, only occurring in 0.89–5% of women [10,11]. Therefore, the benefit from reducing a woman's risk of ovarian cancer may be outweighed by increased risks of CHD and neurologic conditions.

The decision to remove or conserve ovaries most often hinges on the gynecologist's recommendation, with patient age and family history of ovarian or breast cancer used as determining factors. There is uniform agreement that women with known genetic mutations that increase the risk of ovarian and breast cancer (i.e., BRCA1 or BRCA2 mutations) should strongly consider oophorectomy following childbearing [12]. For women without a genetic mutation or family history of ovarian cancer, current practice suggests that prophylactic oophorectomy is usually not recommended for women under 40 years of age, is recommended routinely for women over the age of 55 years, and recommendations vary greatly among women aged between 40 and 55 years [13]. Ethical principles dictate that prophylactic surgery should not be performed unless there is clear evidence that the benefits outweigh the harms. Therefore, it is important that both women and their healthcare providers have access to the most reliable evidence regarding the potential risks and benefits of prophylactic oophorectomy in order to inform this decision making.

Ovarian cancer prevention

In 2008, there were an estimated 21,650 new cases of ovarian cancer (mean age at diagnosis: 63 years) and 15,520 deaths due to the disease [14]. Unfortunately, there is no reliable screening test for the general population to detect early-stage cancers and most women present with advanced disease when the 5-year survival is 15–25% [15,16]. While the lifetime risk of ovarian cancer is 1.4% among US women overall, the risk varies significantly depending on the prevalence of risk factors. For White women with three or more term pregnancies and 4 or more years of oral contraceptive use, the risk of ovarian cancer by the age of 65 years is 0.3%, compared with 1.6% among nulliparous women with no prior oral contraceptive use [17].

Bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy is an extremely effective strategy for ovarian cancer prevention and some authors have advocated oophorectomy for all women aged 40 years and older who undergo hysterectomy for benign disease [18,19]. One study calculated that 5.2% of ovarian cancers would be prevented in the USA if bilateral oophorectomy was performed at the time of hysterectomy in all women aged 40 years and older [18]. If bilateral oophorectomy was performed during all surgeries in women older than 40 years in which there was easy access to the pelvis, such as tubal ligation, bowel surgery or major urologic surgery, 10.9% of ovarian cancers would be prevented [19]. Using these estimates, approximately 2000 new cases of ovarian cancer could thus be avoided every year by uniformly performing BSO in women aged older than 40 years who are undergoing abdominal or pelvic surgery.

Prevention of future ovarian surgery

Studies have demonstrated that the percentage of women who require reoperation following ovarian conservation is low, between 0.89 and 5.5% [10,11]. Among 2561 women with retained ovaries, the most common causes for reoperation were pelvic pain and the presence of an asymptomatic adnexal mass [11]. Current understanding of the frequent occurrence of asymptomatic benign ovarian cysts in postmenopausal women (prevalence: 6.6%) suggests that these masses often do not need to be removed [20]. In this study, only 0.35% (n = 9) of women were found to have malignant ovarian neoplasms. This rate is consistent with prior studies that reported 0.1–0.75% of women develop ovarian cancer following hysterectomy and ovarian conservation [21,22]. Therefore, the risk of developing either a benign or malignant adnexal mass that requires reoperation is quite low in women who retain ovaries at the time of hysterectomy.

Breast cancer prevention

Breast cancer is the most common cancer among women, with 182,460 new cases estimated in 2008 in the USA [14]. However, using mammography for early detection, the majority of women present with early-stage disease and the overall 5-year survival is 88.7% (Surveillance, Epidemiology and End Results [SEER]) [202]. Two large cohort studies found a 35–50% decreased risk of breast cancer among women who underwent oophorectomy compared with the expected risk of breast cancer in the general population [23,24]. However, in one study, the protective effect was limited to women younger than 50 years of age at the time of surgery and the effect only persisted for 10 years following hysterectomy [24]. The other study only found a protective effect for women aged 35–44 years at the time of surgery [23]. The inability to adjust these analyses for potential confounding factors, such as parity, or menstrual and family history, limits these findings. In addition, several studies found a decreased risk of breast cancer following hysterectomy with ovarian conservation compared with women who did not undergo hysterectomy [25 –27].

Risk of cardiovascular disease

In observational studies, earlier age of surgical or natural menopause has been associated with a higher risk of cardiovascular mortality [28 –30]. Early reports from the Nurses' Health Study found that oophorectomy for women who never used estrogen doubled the risk of myocardial infarction (MI; relative risk [RR]: 2.2; 95% CI: 1.2–4.2). However, the study group was compared with age-matched premenopausal women, rather than women having a hysterectomy but with ovarian conservation [31]. Even after 50 years of age, oophorectomy has been demonstrated to increase the risk of developing a first MI compared with controls, although these results barely missed statistical significance (RR: 1.4; 95% CI: 1.0–2.0) [32]. One published meta-analysis of observational studies found that oophorectomy doubled the risk of cardiovascular disease (RR: 2.62; 95% CI: 2.05–3.35), although some studies included in the analysis used surrogate outcomes or were of poor quality [5].

A recent systematic review attempted to overcome these limitations and found mixed evidence for the risk of CHD following BSO [33]. The authors concluded that the current literature precludes a definitive recommendation for BSO practice considering the mixed data on CHD outcomes. After a review of 1956 citations, seven were included in the final analysis and only one was categorized as high-quality evidence. Overall, oophorectomy compared with hysterectomy with ovarian preservation was not associated with an increased risk of CHD [34,35]. Compared with women who had gone through natural menopause, one study found a slight increased risk of CHD among women who underwent oophorectomy, but two studies did not confirm these findings [35 –37]. Oophorectomy was associated with an increased risk of CHD compared with premenopausal women, but only in some subgroups of women or in certain limited analyses [31,35]. Compared with women who never underwent hysterectomy, one study found an increased risk of CHD following BSO, but the other did not [38,39]. Overall, four studies found an increased risk of CHD following BSO, but only in some subgroups of women. Three studies found no increased risk for CHD, although these studies had significant limitations.

A study subsequently published from the Mayo Clinic, MN, USA, found that when looking at the underlying cause of death only, mortality was not increased in women who underwent bilateral oophorectomy before menopause compared with referent women in the overall sample [40]. However, further analyses considering all causes of death listed on the death certificate reported a significant association between bilateral oophorectomy before 45 years of age and cardiovascular mortality (hazard ratio [HR]: 1.44; 95% CI: 1.01–2.05). Within this age range, the risk was significantly increased in women who were not treated with estrogen by age 45 years but not in women treated with estrogen.

Indirect evidence supports an increased risk of cardiovascular disease following oophorectomy. Data from the Women's Health Initiative (WHI) demonstrated that hysterectomy with oophorectomy was an independent predictor of Framingham risk score, which has been shown to predict MI or coronary death [41]. Reduction in endogenous estrogen has been demonstrated to increase serum lipids, reduce carotid artery blood flow and increase subclinical atherosclerosis as measured by carotid artery intima-media thickness [42 –44]. Women having earlier menopause as a result of bilateral oophorectomy have elevated subclinical atherosclerosis compared with same-age women who had natural menopause [45].

Lower endogenous androgen levels were also associated with an increased risk of both CHD and stroke [46]. Although not investigated in humans, estrogen has been demonstrated to be neuroprotective in animals and cell culture, suppressing inflammation and facilitating regeneration of vascular endothelium [47].

Osteoporosis & hip fracture

Ovarian hormones play important roles in bone metabolism considering that both estrogens and androgens inhibit bone resorption and androgens also stimulate bone formation [48]. Oophorectomy or early natural menopause are both considered important risk factors for the development of osteoporosis and hip fracture [49]. Studies document that women who had bilateral oophorectomy had significantly lower levels of androgens and estrogens compared with naturally menopausal women, and low levels of these hormones are linked to lower bone density and greater risk of hip and vertebral fractures in postmenopausal women [50 –55].

Less well appreciated, however, are the studies in older, postmenopausal women that demonstrate an increased risk of osteoporosis following bilateral oophorectomy. Over 16 years of follow-up, 340 postmenopausal women who had an oophorectomy for benign conditions (median age at surgery: 62 years) had 54% more osteoporotic fractures than those with intact ovaries [56]. The authors concluded that the findings supported the hypothesis that androgens produced by the postmenopausal ovary are important and protect against fracture risk. However, two other studies found no association of oophorectomy with bone loss or fracture risk in postmenopausal women [57,58].

Indirect evidence supports an adverse effect of oophorectomy performed after menopause on bone metabolism. Serum and urinary markers of bone resorption as well as bone density were measured in 80 menopausal women divided into four groups as follows: 3 years or less since natural menopause; 3 years or more since natural menopause; 3 years or less since oophorectomy; and 3 years or more since oophorectomy [59]. Serum markers of bone resorption were significantly higher in the 3 years or less since oophorectomy group and the lowest lumbar BMD was found in the 3 years or more since oophorectomy group. The authors concluded that women are at the greatest risk of bone resorption during the first few years following oophorectomy and that bone loss following oophorectomy is greater than that observed following natural menopause [59].

Importantly, hip fracture is a well-documented cause of increased morbidity and mortality in older women. A study of patients' ability to function demonstrated that before hip fracture, 28% of patients were house-bound, but 1 year later 46% were house-bound [60]. Of the patients walking unaided before hip fracture, only 40% were able to walk without a cane or walker 1 year later. Since oophorectomy may result in higher rates of osteoporosis and hip fracture compared with natural menopause, oophorectomy may place women at higher risk of mortality from hip fracture. In a prospective cohort study, women older than 60 years of age with oophorectomy had a twofold increase in mortality after low trauma hip fracture when compared with women with intact ovaries (OR: 2.18; 95% CI: 2.03–2.32) [56]. A 5-year prospective cohort study calculated that women suffering low-trauma osteoporotic hip fractures between the ages of 60 and 64 years lost 11 years of life and those with fractures between ages 70 and 74 years lost 4.4 years [61].

Mood, sexuality & quality of life

Following removal of both ovaries in a premenopausal woman, there is a sudden loss of estrogen, often triggering severe symptoms of hot flashes, mood changes, sleep disturbances, headaches and a decline in feelings of wellbeing [62,63]. Over time, other menopausal symptoms may occur, including vaginal dryness, painful intercourse, loss of libido, bladder dysfunction and symptoms of depression [64,65]. The incidence and severity of these symptoms are increased in women who have had bilateral oophorectomy compared with naturally menopausal women [66]. In addition, following oophorectomy these symptoms occur at an earlier age and may be more difficult to treat with hormonal therapy.

More than 90% of premenopausal women will have vasomotor symptoms following oophorectomy [67]. A survey of 475 postmenopausal women aged 40–60 years found that women who had hysterectomy with ovarian conservation or had natural menopause had a lower risk of experiencing hot flashes than women who had hysterectomy and oophorectomy [68]. The immediate effects of oophorectomy on cognitive thought, memory, energy level, mood and feelings of wellbeing have been documented in perimenopausal women within a few weeks following oophorectomy, but were unchanged in women undergoing hysterectomy alone [69,70].

Genital symptoms associated with estrogen deficiency are decreased vaginal lubrication, itching, dryness, burning and discharge. Long-term estrogen and androgen deficiencies can lead to progressive thinning of the vaginal epithelium, loss of glycogen and resultant loss of Lactobacilli. Loss of Lactobacilli allows the vaginal pH to rise, making the tissue more vulnerable to vaginal and urinary tract infections. Over time, these changes can also result in fissures, ecchymoses and ulcerations [71]. Up to 40% of all postmenopausal women have bothersome symptoms of atrophic vaginitis, including recurrent vaginitis, painful intercourse, pruritis and possibly vaginal stenosis [71]. Changes affecting the urethral and bladder epithelium can cause a sensation of bladder pressure, urethral discomfort, dysuria, urinary frequency and recurrent urinary tract infections. Studies document increased incidence of urogential atrophy in surgically menopausal women compared with naturally menopausal women, perhaps related to low levels of ovarian androgens [71,72].

There is now some evidence that sexual desire and motivation in women are dependent on androgens [73]. In addition, androgens appear to impact sexual sensation and orgasmic response [74]. Declines in sexual desire are reported in women who have elective oophorectomy at the time of hysterectomy, but not for women who have hysterectomy and ovarian conservation [75]. The declines in sexual function following oophorectomy were reversed following estrogen and androgen therapy and partially restored following treatment with estrogen alone.

Another study assessed health-related quality-of-life outcomes and sexual functioning among premenopausal women having hysterectomy with and without BSO. After 6 months postsurgery, scores for the oophorectomy group showed less improvement in mental health measures and body image compared with women with ovarian conservation, although there were no differences in hot flashes between groups. However, after 2 years of follow-up, the levels of improvement for these outcomes, as well as all other measures of health-related quality-of-life and sexual functioning, were similar. [76]

Sexual function following oophorectomy has been well-studied in women with a high risk of hereditary ovarian cancer. Compared with before surgery, these women reported significantly lower menopause-specific quality-of-life scores following prophylactic oophorectomy and 42–53% of the participants reported that their satisfaction with sexual functioning was moderately to extremely compromised [74].

Long-term health outcomes & mortality

In order to broadly examine the overall risks and benefits of oophorectomy at the time of hysterectomy, a decision analysis was performed using data from previously published observational studies. The analysis found that, in hypothetical groups of healthy women aged 40–65 years (without a family history of ovarian cancer) who have a hysterectomy for benign disease, ovarian conservation maximized survival [77]. For women younger than 55 years of age who had a hysterectomy, calculations suggested that 8.6% more women who had ovarian conservation would be alive at the age of 80 years.

A study from the Mayo Clinic found that all-cause mortality was not increased in women who underwent bilateral oophorectomy before menopause compared with referent women in the overall sample [40]. However, all-cause mortality was significantly higher in women who had prophylactic bilateral oophorectomy before the age of 45 years compared with referent women (HR: 1.67; 95% CI: 1.16–2.40). The association was particularly strong in women who had bilateral oophorectomy before the age of 45 years and did not receive estrogen treatment up to the age of 45 years (HR: 1.93; 95% CI: 1.25–2.96).

The Mayo Clinic study found the risk of death to be significantly increased from both estrogen-related cancers and all other noncancer causes. In addition, mortality from neurological or mental disorders was significantly increased in this group [78].

In order to further examine long-term health outcomes, the Nurses' Health Study cohort database was analyzed, which included 122,700 married registered nurses who were aged 30–55 years in 1976 when the initial questionnaires were mailed [79]. The nurses involved in the cohort were predominantly White (94%) and were relatively homogeneous with regard to education, socioeconomic status and access to healthcare [31]. Women were excluded if they had a diagnosis of gynecologic cancer prior to or concurrent with hysterectomy, an oophorectomy prior to or subsequent to hysterectomy, a unilateral or partial oophorectomy, an unknown age or ovarian status at the time of hysterectomy, or an outcome of interest prior to surgery. The remaining 29,380 women were included in the analysis; 13,035 (44.4%) had a hysterectomy without oophorectomy (ovarian conservation) and 16,345 (55.6%) had a hysterectomy with bilateral oophorectomy.

During 24 years of follow-up through 2002, nonfatal events and death due to the following conditions were analyzed: CHD, stroke, breast cancer, epithelial ovarian cancer, lung cancer, colorectal cancer, hip fracture, pulmonary embolus and death due to all causes. Risk factors and newly diagnosed health conditions have been updated every 2 years with response rates of 90% and each outcome analysis was adjusted for multiple related risk factors. This study is the largest prospective study, with the longest follow-up, to examine the effect of oophorectomy on health outcomes in women.

With regard to nonfatal events, oophorectomy was associated with an increased risk of CHD for all women (HR: 1.17; 95% CI: 1.02–1.35) and the effect was greater for women who had oophorectomy before the age of 45 years (HR: 1.26; 95% CI: 1.04–1.54). Breast cancer was less frequent among all women who had oophorectomy (HR: 0.75; 95% CI: 0.68–0.84), and the risk was lower among women who had oophorectomy before the age of 45 years (HR: 0.62; 95% CI: 0.53–0.74). Oophorectomy was associated with a markedly reduced risk of ovarian cancer (HR: 0.04; 95% CI: 0.01–0.09) and a slight reduction in the incidence of total cancers (HR: 0.90; 95% CI: 0.84–0.96), but an increased risk of lung cancer (HR: 1.26; 95% CI: 1.02–1.56). Risks of stroke, hip fracture, colorectal cancer and pulmonary embolism did not differ significantly between groups.

With regard to fatal events, oophorectomy increased the risk of death from any cause (HR: 1.12; 95% CI: 1.03–1.21). Analysis of cause-specific mortality found an increased risk of death from CHD (HR: 1.28; 95% CI: 1.00–1.64), lung cancer (HR: 1.31; 95% CI: 1.02–1.68) and all cancers (HR: 1.17; 95% CI: 1.04–1.32) and no overall difference in deaths from stroke, breast cancer or colorectal cancer. While there was a reduced risk of death from ovarian cancer (HR: 0.06; 95% CI: 0.02–0.21), during the 24 years of follow-up, only 34 (0.7%) women died from ovarian cancer. At no age did oophorectomy show a survival benefit.

A separate analysis was performed for women who had never used postmenopausal hormones. For all women having bilateral oophorectomy, the risks of stroke (HR: 1.85; 95% CI: 1.09–3.16) and lung cancer (HR: 2.09; 95% CI: 1.01–4.33) were higher. For women who underwent oophorectomy before the age of 50 years, the risk of incident CHD (HR: 1.98; 95% CI: 1.18–3.32) was higher, as was the risk of death from all causes (HR: 1.40; 95% CI: 1.01–1.96).

The Nurses' Health Study cohort is particularly homogenous relative to a study in the general population, with regard to educational and socioeconomic factors that may possibly confound nonrandomized studies. However, the study was observational and oophorectomy or ovarian conservation was still self-selected. In order to reduce the possibility of confounding, women with any prior diagnosis of cancer or unilateral oophorectomy were excluded from the analysis and it was adjusted for family history of breast or ovarian cancer. Although baseline characteristics differed somewhat between groups, multivariable analysis was used to correct for multiple known risk factors associated with all the conditions of interest. However, the findings may still be due to uncorrected differences between the groups. In addition, most of the women in this study were White and the results may not be applicable to non-White women.

While estrogen therapy may reduce some of the increased risks in women following oophorectomy, subsequent to publication of the WHI findings many women discontinued hormone therapy and 77% fewer women now start hormones at the time of menopause [80]. Considering that 300,000 women per year undergo elective oophorectomy, these findings of increased long-term risks have important public health implications.

Neurologic conditions: Parkinsonism, dementia & cognitive impairment, anxiety & depression

Analysis of data from the Mayo Clinic Cohort Study of Oophorectomy and Aging led to the publication of three studies that suggest an association between oophorectomy and increased risks of Parkinsonism, dementia and cognitive impairment, and anxiety or depression [6 –8].

The study cohort included all women who underwent bilateral oophorectomy (n = 1075) before the onset of menopause for a noncancer indication from 1950 through 1987 while residing in Olmsted County, MN, USA. These women were matched by age to referent women (n = 2368) in the same population who had not undergone oophorectomy. Women were followed through death or the end of each study using a combination of direct or proxy interviews, neurologic examinations, and review of medical records and death certificates. Women were followed for a mean of 25–30 years and approximately 90% completed follow-up.

The studies demonstrate that bilateral oophorectomy before the onset of menopause increased the risk of Parkinsonism (HR: 1.80; 95% CI: 1.00–3.26; overall analysis), cognitive impairment or dementia (HR: 1.70; 95% CI: 1.15–2.51; for oophorectomy before 49 years of age), and anxiety (HR: 2.29; 95% CI: 1.13–3.95; overall analyses) or depression (HR: 1.54; 95% CI: 1.04–2.26; for depression ever diagnosed by a physician). For all of these conditions, the risk was increased with younger age at oophorectomy and was independent of the indication for oophorectomy. Regarding dementia, women who underwent bilateral oophorectomy before the age of 49 years, but were given estrogen treatment until at least 50 years of age, had no increased risk.

The Mayo Clinic studies have some limitations:

The studies were observational studies and unrecognized confounding variables cannot be excluded;

Documentation of cognitive impairment or dementia was limited to telephone information;

The screening instrument for Parkinsonism was imperfect, and not all women who screened positive could be examined during the study;

Although the studies had adequate power for overall analyses, several of the stratified analyses and analyses for age trends had limited power;

The comparison group was women who did not have oophorectomy, not women who had a hysterectomy with ovarian preservation;

The population of Olmsted County is primarily White of European ancestry, and the findings may not apply to other populations.

Although women who reported a history of depressive symptoms before the index year were excluded from depressive symptoms analyses and those who reported a history of anxiety symptoms were excluded from anxiety symptoms analyses, women with clinically recognized depressive or anxiety symptoms may be more likely to choose to undergo prophylactic bilateral oophorectomy when hysterectomy is performed. They may also be more likely to experience a recurrence or exacerbation of depression after surgery [8,81,82].

The combined findings for Parkinsonism, cognitive impairment or dementia, and anxiety or depression suggest that the neuroprotective effect of estrogen may involve multiple mechanisms and multiple neuronal populations. Estrogen has been demonstrated to have neuroprotective effects in animal models of Parkinson disease, to reduce oxidative stress and upregulate neurotrophic factors, and is protective of dopaminergic neurons in primate models. However, while surgical menopause was linked to increased risk of Parkinson disease in one clinical study, this association was not found in two other studies [83,84].

With regard to cognitive impairment or dementia: estrogen improves synapse formation on dendritic spines in hippocampi of oophorectomized rats; it may improve cerebral blood flow and glucose metabolism; it may act as an antioxidant; it increases choline acetyltransferase activity in the basal forebrains and hippocampi of oophorectomized rats; it reduces the deposition of β-amyloid in the brain; and it prevents mitochondrial damage [85 –92]. Although three meta-analyses demonstrated a 20–40% reduction in risk of Alzheimer disease for women who used estrogen treatment after menopause, the WHI found an increased risk of dementia or mild cognitive impairment in women treated by either estrogen alone or estrogen plus progestin after the age of 65 years [93 –102]. One explanation for these disparate findings is that estrogen may have a protective effect on the brain if given to women shortly after natural menopause or if given to women who undergo oophorectomy before menopause. By contrast, estrogen may have deleterious effects on the brain if started many years after the onset of natural menopause. Thus, there may be a critical age window for neuroprotection [103].

Despite limitations in methodology and low statistical power, the Mayo Clinic studies support the hypothesis of a critical age window for the protective effect of estrogen on the brain in humans. However, the authors suggest that independent replication of the findings is necessary before they can guide gynecological practice.

Other studies of endogenous estrogen and cognitive function are few and yield inconsistent results. One study found that among women not using estrogen, there were no significant differences on mean cognitive function scores by hysterectomy and oophorectomy status [104]. Among current estrogen users, after adjustment for age, education, age at menopause and past estrogen use, women with a hysterectomy and bilateral oophorectomy performed less well on cognitive function tests compared with women with ovarian conservation, although the differences were small and unlikely to be of clinical significance. No differences in cognitive function were observed between women who had a hysterectomy with ovarian conservation and women with both uterine and ovarian conservation. However, the sample size of that study was relatively small and oophorectomies performed before or after menopause were not distinguished. Two additional small studies suggested that bilateral oophorectomy may cause short-term cognitive impairment [69,105].

Conclusion

In general, decision-making regarding ovarian preservation, oophorectomy and hormone-replacement therapy is complex and difficult. Nevertheless, recent studies suggest that a more detailed informed consent process covering the risks and benefits of oophorectomy and ovarian conservation is necessary. Prophylactic surgery should be performed only if there is evidence that it clearly benefits the patient. At present, observational studies suggest that bilateral oophorectomy may do more harm than good. Until well-designed, prospective, randomized studies are conducted that compare women undergoing hysterectomy with ovarian conservation with women undergoing hysterectomy and oophorectomy, removing the ovaries at the time of hysterectomy should be approached with caution.

Limitations of the current literature & future perspective

The entire body of evidence that examines both the risks and benefits of BSO is derived from observational studies, which by design have significant inherent limitations [106]. Observational studies are prone to bias owing to the differential distribution of factors, known and unknown, that are associated with both the probability of undergoing a oophorectomy and the outcome of interest. In addition, a myriad of factors may be involved in the decision to undergo oophorectomy at the time of hysterectomy, including age, indication for hysterectomy, the presence of menopausal symptoms or depression, comorbidities, family history of cancer or heart disease, the desire to use postoperative hormones, or sexual functioning and partner status. All of these factors may influence one or more of the diverse range of health outcomes that have been examined following oophorectomy, including cardiovascular disease, bone health, cognitive function and cancer, as well as mood, sexual functioning and quality of life. Therefore, the presence of significant confounding in the observational literature is highly probable and may explain the heterogeneity in results in the existing literature that has examined oophorectomy outcomes.

Executive summary

Approximately 300,000 US women have prophylactic bilateral oophorectomy at the time of hysterectomy every year.

Ovarian cancer prevention

In 2008, there were an estimated 15,520 deaths due to ovarian cancer.

Bilateral salpingo-oophorectomy at the time of hysterectomy is an extremely effective strategy for ovarian cancer prevention.

Prevention of future ovarian surgery

Only 0.1–0.7% of women develop ovarian cancer following hysterectomy and ovarian conservation.

Reoperation following ovarian conservation is rare, with rates between 0.89 and 5.5%.

Breast cancer prevention

Oophorectomy may decrease the risk of breast cancer by 35–50%, but the protective effect may be limited to women younger than 50 years of age at the time of surgery and may only persist for 10 years following surgery.

Risk of cardiovascular disease

Oophorectomy in women who never used estrogen has been found to increase the risk of myocardial infarction compared with age-matched premenopausal women.

However, a recent systematic review found mixed evidence for the risk of coronary heart disease (CHD) following bilateral salpingo-oophorectomy.

Osteoporosis & hip fracture

Postmenopausal women who had an oophorectomy have been found to have 54% more osteoporotic fractures than those with intact ovaries.

However, two studies found no association of oophorectomy with bone loss or fracture risk in postmenopausal women.

Mood, sexuality & quality of life

Removal of both ovaries in a premenopausal woman often triggers severe symptoms of hot flashes, mood changes, decline in feelings of wellbeing, sleep disturbances and headaches.

Over time, vaginal dryness, painful intercourse, loss of libido, bladder dysfunction and symptoms of depression may occur.

Neurologic conditions: Parkinsonism, dementia & cognitive impairment, anxiety & depression

Bilateral oophorectomy before the onset of menopause increases the risk of Parkinsonism, cognitive impairment and dementia, and anxiety or depression.

For all of these conditions, the risk was increased with a younger age at oophorectomy.

Women who underwent bilateral oophorectomy before the age of 49 years, but were given estrogen treatment until at least 50 years of age, had no increased risk of dementia.

Long-term health outcomes & mortality

Of the 29,380 women in the Nurses' Health Study cohort who had a hysterectomy, 13,035 (44.4%) did not have a bilateral oophorectomy and 16,345 (55.6%) had a hysterectomy with bilateral oophorectomy.

Oophorectomy was associated with an increased risk of CHD for all women.

Ovarian cancer and breast cancer were less frequent among all women who had undergone oophorectomy.

Oophorectomy significantly increased the risk of lung cancer.

Risks of stroke, hip fracture, colorectal cancer and pulmonary embolism did not differ significantly between groups.

Oophorectomy increased the risk of death from any cause, including an increased risk of death from CHD, lung cancer and all cancers.

During the 24 years of follow-up, only 34 (0.7%) women died from ovarian cancer.

At no age did oophorectomy show a survival benefit.

Women who had bilateral oophorectomy and had never used postmenopausal hormones had increased risks of stroke and lung cancer.

Never-users of postmenopausal hormones who had bilateral oophorectomy before 50 years of age had increased risks of incident CHD and death from all causes.

Limitations of the current literature & future perspective

The entire body of evidence that examines both the risks and benefits of oophorectomy is derived from observational studies, which have significant inherent limitations.

A pilot multicentered, randomized trial of oophorectomy versus ovarian conservation at the time of hysterectomy is being conducted to examine short-term outcomes for cardiovascular health, bone health, menopausal symptoms, sexual functioning and health-related quality of life.

A more detailed informed consent process covering the risks and benefits of oophorectomy and ovarian conservation is necessary.

Observational studies suggest that bilateral oophorectomy may do more harm than good.

Well-designed clinical studies are needed to explore the specific effects of bilateral oophorectomy on the long-term health of women. Cohorts with long periods of follow-up after oophorectomy are few and studies with shorter follow-up may not be adequate to address these issues.

There are currently no randomized trials of BSO to provide the highest quality evidence to guide surgical decision-making, and cohorts with long follow-up after oophorectomy are few. While there may be significant challenges to conducting a randomized trial, including patient recruitment and the development of feasible and appropriate clinical outcomes with reasonable follow-up time, a well-designed, randomized trial should overcome the significant biases that have influenced the current literature. At present, a pilot multicentered, randomized trial of BSO versus ovarian conservation at the time of benign hysterectomy is being conducted with short-term outcomes for cardiovascular health, bone health, menopausal symptoms, sexual functioning and health-related quality of life [Jacoby V, Pers. Com. May 2009].

New laboratory and clinical research studies are needed to clarify the hormonal mechanisms and any possible genetic interactions responsible for the effect oophorectomy may have on women's health with regard to the cardiovascular effects, as well as lung, bone and all-cause cancer effects. Studies on the effects of estrogen, progesterone, testosterone, luteinizing hormone and follicle-stimulating hormone on the brain may provide new strategies for the prevention and treatment of aging-related neurological diseases.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Effect of Bilateral Oophorectomy on Women's Long-Term Health

Abstract

Keywords

Ovarian cancer prevention

Prevention of future ovarian surgery

Breast cancer prevention

Risk of cardiovascular disease

Osteoporosis & hip fracture

Mood, sexuality & quality of life

Long-term health outcomes & mortality

Neurologic conditions: Parkinsonism, dementia & cognitive impairment, anxiety & depression

Conclusion

Limitations of the current literature & future perspective

Footnotes

References