INTRODUCTION — Hysterectomy (surgical removal of the uterus) is the second most common major surgical procedure (cesarean section is the most common) performed among women in the United States [1]. Patients undergo oophorectomy at the time of hysterectomy less frequently than in the past [2,3]. A 2005 United States nationwide study reported that unilateral or bilateral oophorectomy was performed in 68 percent of patients at the time of abdominal hysterectomy, 60 percent at laparoscopic hysterectomy, and 26 percent at vaginal hysterectomy [4]. A study from 2013 to 2014 showed that 44 percent of patients younger than 51 years had oophorectomy at the time of hysterectomy for benign disease (outcomes were: normal ovaries 23 percent, ovarian cancer 0.2 percent, and benign pathology 21 percent). Although the total number of hysterectomies with oophorectomies among premenopausal patients has decreased, the percentage of oophorectomies with no reason for removal has disproportionately remained stable in California (38 percent), with significant racial disparities appreciated [3].
Historically, it had been common practice to counsel patients in their mid-40s or older who were planning hysterectomy for benign indications to undergo concomitant bilateral salpingo-oophorectomy [5]. The rationale for this approach was that oophorectomy greatly decreases the risk of ovarian cancer and the need for future ovarian surgery and that there is little advantage of ovarian preservation, since patients in this age range are close to or beyond menopause. This approach also assumed nearly universal treatment with postmenopausal hormone therapy.
A growing understanding of the potential long-term health risks of elective oophorectomy and potential advantages of elective salpingectomy in premenopausal patients has changed clinical practice [6,7]. In the setting of benign disease, the decision to retain or remove tubes and ovaries should be based upon the long-term health effects. The pendulum has swung toward ovarian conservation in patients under age 51 [8].
For patients with a gynecologic malignancy, there are often clear indications for salpingo-oophorectomy. For those at high genetic risk of ovarian cancer, risk-reducing salpingo-oophorectomy or salpingectomy may be indicated.
An evidence-based approach to management of the tubes and ovaries at the time of hysterectomy for benign disease will be reviewed here. Techniques for salpingectomy and oophorectomy, risk-reducing salpingectomy and oophorectomy for patients with a hereditary ovarian cancer syndrome, and general principles of menopause are discussed separately. (See "Oophorectomy and ovarian cystectomy" and "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer" and "Clinical manifestations and diagnosis of menopause".)
TERMINOLOGY
●Elective salpingo-oophorectomy – Removal of the ovaries and fallopian tubes in a patient who has no known indication for this procedure (eg, ovarian pathology, hereditary ovarian cancer syndrome). Ovaries and tubes are typically removed, rather than the ovaries alone.
●Risk-reducing salpingo-oophorectomy – Removal of the ovaries and fallopian tubes in a patient with a hereditary ovarian cancer syndrome. Risk reduction requires removal of the tubes as well as the ovaries because some malignancies currently categorized as ovarian cancers may arise in the tubal epithelium. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer".)
●Risk-reducing salpingectomy – Removal of just the fallopian tubes in a patient with a general population risk of ovarian cancer syndrome. Risk reduction removes the tubes because many malignancies currently categorized as ovarian cancers may arise in the tubal epithelium.
The term prophylactic salpingo-oophorectomy has been used inconsistently, and so will not be used in this review, except when it was the term used in a particular study. It has been used variously to refer to salpingo-oophorectomy for the prevention of ovarian cancer in either patients at an average risk or those with a hereditary ovarian cancer syndrome [9,10].
SURGICAL EFFECTS ON OVARIAN FUNCTION
Surgical menopause — The ovary is an endocrine organ, with widespread physiologic effects during the postmenopausal, as well as the reproductive, years.
In patients who have not previously undergone natural menopause, bilateral oophorectomy or remaining oophorectomy (removal of an ovary in a patient who has previously undergone unilateral oophorectomy) results in surgical menopause. The rapid change in the reproductive hormonal milieu and abrupt symptom onset that occurs in surgical menopause contrasts with the typical gradual waxing and waning in the hormonal profile and concomitant menopausal symptoms that occur in natural menopause.
Surgical menopause results in an abrupt drop in estrogen levels, an abrupt rise in follicle-stimulating hormone (FSH) level, and the complete cessation of ovarian hormone production, including androgens, estradiol, and progesterone [11-13].
By contrast, the transition into natural menopause is characterized by variable estradiol and FSH levels, in association with unpredictable ovulatory and anovulatory cycles. The variability in hormone levels is most dramatic over a period of four years, and typically continues over an interval of up to 10 years [14,15]. Ultimately, estrogen levels remain low and FSH levels high, but there is no specific hormone level profile that unequivocally characterizes the onset of natural menopause. Intact postmenopausal ovaries continue to be hormonally active for many years beyond menopause, producing androgens including testosterone, androstenedione, and dehydroepiandrosterone (DHEA), as well as very small amounts of estradiol and estrone [16]. Although estrogen secretion by the postmenopausal ovary eventually ceases, ovarian secretion of small amounts of testosterone and the androgen precursor, DHEA, may continue into the eighth decade of life [12,16].
Extraovarian sources of sex steroids throughout life include the adrenal glands and widespread target tissues, including fat, where aromatization of androgens into estrogen occurs. The extent to which extraovarian sex steroid hormone synthesis differs between patients who have experienced natural versus surgical menopause has been debated [12,13], but it appears that total androgen levels remain lower after surgical menopause than after natural menopause [12].
Early menopause following hysterectomy — Hysterectomy appears to alter ovarian function over the long term, even if the ovaries are conserved. This effect is incompletely understood but is possibly due to impairment of the ovarian blood supply or other yet unknown mechanisms [17-19]. Observational studies have found that patients who undergo hysterectomy develop menopausal symptoms and changes in hormone profiles earlier than controls who did not have a hysterectomy. As an example, a prospective cohort study found that menopause (defined as FSH ≥40 international units/L) occurred 3.7 years earlier in premenopausal patients who had a hysterectomy (both ovaries retained) compared with those who did not have a hysterectomy [19]. And, among all patients who underwent hysterectomy, those who had only one ovary conserved reached menopause 4.4 years earlier than those who had both ovaries conserved.
INDICATIONS FOR OOPHORECTOMY — Patients who undergo hysterectomy for benign indications may also have an indication for concurrent oophorectomy. Oophorectomy in this context is not elective. However, even in this circumstance, the risk-to-benefit balance of bilateral oophorectomy should be considered.
Ovarian pathology is the usual indication for oophorectomy (eg, ovarian neoplasms). These indications are reviewed separately. (See "Oophorectomy and ovarian cystectomy", section on 'Oophorectomy versus cystectomy'.)
Some patients with extraovarian pathology may also benefit from oophorectomy, including:
●Endometriosis – The risk of reoperation for endometriosis-related concerns appears to be lower if the ovaries are removed at the time of hysterectomy [20]. (See "Endometriosis: Treatment of pelvic pain", section on 'Surgical treatment options'.)
●Tubo-ovarian abscess – In patients requiring surgical management of tubo-ovarian abscess, the risk of reoperation is higher if one or both ovaries are conserved [21]. (See "Management and complications of tubo-ovarian abscess", section on 'Drainage and surgery'.)
●Pelvic adhesions/pelvic pain – The incidence of residual ovary syndrome, characterized by posthysterectomy pelvic pain, is 0.9 to 3.4 percent [22]. Subsequent oophorectomy may be required to manage such symptoms. Preoperative pelvic pain and adhesions are risk factors for this syndrome. Thus, hysterectomy with bilateral salpingo-oophorectomy has been a common approach for such patients [23].
STUDIES REGARDING ELECTIVE OOPHORECTOMY — The highest quality data regarding long-term health outcomes of elective oophorectomy compared with ovarian conservation at time of surgery are from two large, prospective studies and two retrospective studies discussed below; no randomized trial has investigated this issue [24]:
●The Nurses' Health Study (NHS) was a prospective cohort study that included 29,380 women who had a hysterectomy for benign disease [25,26]. The average age at time of surgery was approximately 43 to 47 years and the average age at enrollment was 51 years, 94 percent were White, and subjects were followed for 28 years.
●The Women's Health Initiative (WHI) Observational Study was a prospective study that included 25,448 women who had a hysterectomy for benign disease [27]. Subjects in this study were initially invited to participate in the WHI randomized trial that evaluated postmenopausal hormone therapy but were either found ineligible or declined to participate in the trial. The average age at time of hysterectomy was 49 years or younger, and the average age at enrollment was 63 years, 82 percent were White, and subjects were followed for an average of only eight years. One limitation of this study includes the potential for recall bias, which likely affects the risk estimates.
●A retrospective study of data from a United Kingdom national database evaluated 113,679 patients ages 35 to 45 years old who underwent hysterectomy for benign conditions from 2004 to 2014 [28].
●The Mayo Clinic Cohort Study of Oophorectomy and Aging (MOA) was a retrospective population-based cohort study of 2365 patients in Olmstead County, Minnesota who underwent unilateral or bilateral oophorectomy for benign disease; almost all were White [29,30]. For some analyses, patients from the cohort were compared with controls who had not had an oophorectomy and were identified via random digit telephone dialing [31]. The median age at time of surgery was 44 years among premenopausal patients who had a bilateral oophorectomy and 62 years among postmenopausal patients. Patients who had a bilateral oophorectomy were followed for an average of 25 years; 95 percent had the oophorectomy at the time of hysterectomy. Although this study was retrospective, it includes prospective data from centralized medical records regarding the surgical, pharmacy, and outcome data for all participants. Thus, recall bias was limited and there was access to long-term follow-up data.
Findings from these studies, as well as from other relevant studies, are reviewed in the sections that follow. Data from the WHI conflict with data from the NHS and the Mayo Clinic Cohort Study regarding many outcomes, including risk of all-cause mortality, cardiovascular disease (CVD) and osteoporotic fractures. We regard the NHS as having the best available data, based upon several methodologic limitations of the WHI Observational Study. Both the NHS and the Mayo Clinic Cohort Study had long follow-up periods (28 to 30 years), adequate to assess outcomes that are more common for patients over age 60 years: CVD and stroke, chronic kidney disease, dementia, osteoporosis, breast cancer, ovarian cancer and all-cause mortality, and shorter gaps between oophorectomy and enrollment. By contrast, patients in the WHI were followed for only a mean of 8 years with an average gap of 14 years from oophorectomy to enrollment. The average age at enrollment in the WHI Observational Study was 63 years. Thus, patients who had outcomes of interest (CVD and stroke, dementia, osteoporosis, breast cancer, ovarian cancer and all-cause mortality) that occurred during the interval from hysterectomy to enrollment were not included, introducing a significant survivor bias to the analysis. Finally, the WHI Observational Study reported that bilateral salpingo-oophorectomy did not have significant adverse effects on all-cause mortality, coronary heart disease, hip fracture, or cancer, but the study has insufficient statistical power to detect differences for these outcomes.
BENEFITS OF ELECTIVE OOPHORECTOMY
Ovarian cancer risk reduction — Bilateral salpingo-oophorectomy (BSO) reduces, but does not eliminate, the risk of developing ovarian cancer. Ovarian-like cancers of the peritoneum, known as peritoneal cancer, may develop after oophorectomy. Oophorectomy performed for ovarian cancer risk reduction should include removal of the fallopian tubes since occult primary fallopian tube cancers have been reported in patients undergoing risk-reducing BSO. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis", section on 'Incidental finding'.)
BSO is an important risk reduction strategy for patients who are at high risk of ovarian cancer. The lifetime risk of ovarian cancer in the general population is 1.2 percent compared with 13 to 46 percent in patients with BRCA1 or BRCA2 gene mutations (table 1), and up to 38 percent in those with Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome), depending on the underlying genetic variant (table 2). Salpingo-oophorectomy in these patients is considered risk-reducing and not elective. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer" and "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer" and "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2".)
The degree of ovarian cancer risk reduction from hysterectomy with BSO in the general population was illustrated in prospective data from the Nurses' Health Study (NHS) [26] (see 'Studies regarding elective oophorectomy' above). The analyses were adjusted for family history of ovarian cancer and duration of oral contraceptive use. Patients who underwent oophorectomy had significant reductions in ovarian cancer mortality compared with those who conserved their ovaries (hazard ratio [HR] 0.06, 95% CI 0.02-0.17). Similar results were reported by the Women's Health Initiative (WHI) Observational Study, another large prospective cohort study, in which the number needed to treat to avoid one case of ovarian cancer was 323 [27].
In a subsequent cohort study including over 195,000 patients undergoing hysterectomy between 1996 and 2010 in Canada, those undergoing BSO (24 percent of patients) compared with ovarian (and tubal) conservation had a decreased incidence of ovarian cancer (HR 0.23, 95% CI 0.14-0.38); the number needed to treat to avoid one case of ovarian cancer was 260 [32]. In a subgroup analysis including patients ≥50 years, the number needed to treat was even lower (161). This study did not include patients who received bilateral salpingectomy with ovarian preservation at the time of hysterectomy in the analysis.
The decision regarding BSO at time of hysterectomy is more difficult for patients who have some risk factors for ovarian cancer (table 3), but who do not have, or have not been tested for, a hereditary ovarian cancer syndrome. Patients for whom a familial cancer syndrome is suspected should be offered genetic counseling and testing (table 4 and table 5). Counseling of patients who have some of the known risk factors for ovarian cancer, but who do not meet criteria for a high risk of ovarian cancer, must be individualized and should include review of all advantages and disadvantages of the procedure. This is an area of uncertainty in which further research is needed to guide the practice. (See "Cancer risks and management of BRCA1/2 carriers without cancer".)
Alternatives to BSO for ovarian cancer risk reduction — Surgical procedures other than BSO may reduce the risk of ovarian cancer, without resulting in surgical menopause.
Procedures that interrupt or remove the fallopian tubes appear to reduce the risk of ovarian cancer but not to the same extent as BSO. Hysterectomy alone was associated with a 34 percent reduction in the risk of ovarian cancer in a meta-analysis of 12 case-control studies [33,34]. Tubal ligation was found to be associated with a 34 percent reduction in ovarian cancer risk in a meta-analysis of case-control studies [35].
Bilateral salpingectomy alone without oophorectomy has also been proposed to decrease the risk of ovarian cancer [6,7,36,37]. The Society of Gynecologic Oncology (SGO) suggests that, for patients at average risk of ovarian cancer, risk-reducing salpingectomy should also be discussed and considered with patients at the time of abdominal or pelvic surgery, hysterectomy, or in lieu of tubal ligation [7]. Potential mechanisms for the protective effect of these procedures include the following: (1) eliminating lesions that may have originated in the fallopian tubes; (2) limiting the potential for upward migration of carcinogens through the vagina, cervix, and fallopian tubes into the peritoneal cavity; and (3) providing a cancer screening effect [38,39]. (See "Opportunistic salpingectomy for ovarian, fallopian tube, and peritoneal carcinoma risk reduction".)
Unilateral oophorectomy has not been proven to reduce the risk of ovarian cancer. Although this observation is counterintuitive, available data have not consistently demonstrated that removing half of the tissue at risk results in half the risk of ovarian cancer. A multicenter case-control study of 1031 patients with ovarian cancer who were compared with patients who did not undergo pelvic surgery found no significant decrease in ovarian cancer risk over a period of seven years in those who underwent unilateral oophorectomy either with hysterectomy (1.4 versus 2.6 percent) or without hysterectomy (1.0 versus 1.6 percent) compared with no pelvic surgery [40]. By contrast, a case-control study of 129 patients with ovarian cancer found a significantly decreased rate of ovarian cancer over a period of 16 years in patients who had undergone unilateral oophorectomy (2.9 versus 13.6 percent) [41]. Further study of this issue is needed.
Breast cancer risk reduction — Oophorectomy appears to reduce the risk of breast cancer, although the age at which the benefit occurs is uncertain. The reduced risk of breast cancer is likely due to reduced exposure to estrogen from the premenopausal ovary. This effect is also seen in patients at high risk of breast cancer. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer", section on 'Candidates'.)
●The NHS, a large prospective study, found that oophorectomy was associated with a significant reduction in breast cancer incidence only in patients who underwent the procedure at age 47.5 years or younger [26]. (See 'Studies regarding elective oophorectomy' above.)
●By contrast, the Women's Health Initiative (WHI) Observational Study found a significant reduction in breast cancer risk only in patients who underwent oophorectomy at age <40 who also did not take estrogen therapy [27]. (See 'Studies regarding elective oophorectomy' above.)
●In a retrospective study including over 49,000 patients at average risk for breast cancer undergoing hysterectomy for benign disease, those who also had a BSO had a 14 percent lower risk of developing breast cancer, after controlling for age, race, income, and comorbidities (HR 0.86, 95% CI 0.75-0.98); patients were followed for a median of 54 months [42]. Age-specific rates were lower for breast cancer in patients with BSO in every age group except those ≥60 years. However, all-cause mortality, at any age, was higher for women undergoing BSO compared with hysterectomy alone.
Other cancers — The effect of oophorectomy on the development of other cancers is less clear. In the WHI Observational Study (see 'Studies regarding elective oophorectomy' above), patients undergoing oophorectomy compared with ovarian conservation had similar rates of lung and colorectal cancers [27]. By contrast, in the NHS study (see 'Studies regarding elective oophorectomy' above), patients undergoing oophorectomy had higher rates of lung cancer (HR 1.26, 95% CI 1.02-1.56) but similar rates of colorectal cancers [25]. In a subsequent cohort study evaluating the risk of cancer and premenopausal oophorectomy, those undergoing oophorectomy (1562 patients) compared with age-matched referent controls had a similar risk of lung and colorectal cancers during the 18-year (median) follow-up period [43].
Avoiding the need for subsequent oophorectomy — Reoperation for ovarian pathology, termed residual ovary syndrome, occurs in 3 to 9 percent of patients who retain one or both ovaries after hysterectomy [22,44,45]. The Mayo Clinic Cohort Study of Oophorectomy and Aging is the largest study to report the risk of subsequent oophorectomy following hysterectomy [45]. In this retrospective study including approximately 10,000 subjects, patients with versus without a history of hysterectomy had a higher rate of reoperation for oophorectomy at 30 years of follow-up (9.2 versus 7.3 percent, HR 1.2, 95% CI 1.0-1.4). Among patients with one preserved ovary, the cumulative incidence of subsequent oophorectomy was 4.0 percent at 30 years, and among women with both ovaries intact, the cumulative incidence was 10.6 percent at 30 years. Other studies that reported lower risk of reoperation had short follow-up, were not population based, and lacked a control group [22,44].
Some data suggest that the reoperation rate is higher in patients who undergo abdominal or laparoscopic hysterectomy compared with a vaginal route [46]. The reason for such a difference is uncertain, but it could be that vaginal hysterectomy is typically not performed when ovarian pathology in one or both ovaries is suspected.
In patients who require oophorectomy subsequent to hysterectomy, laparoscopic techniques have reduced the surgical morbidity of such procedures. However, surgical adhesions from prior hysterectomy may make a laparoscopic approach more difficult. One small study reported that 32 of 35 patients with a prior hysterectomy were able to have a successful laparoscopic oophorectomy [23]. Thus, minimally invasive surgery will provide a solution for most patients who develop ovarian pathology following hysterectomy. Therefore, the possible need for subsequent surgery does not appear to justify the deleterious long-term consequences of BSO for most patients undergoing hysterectomy.
RISKS OF ELECTIVE OOPHORECTOMY
Added surgical risk — Operative complications are uncommon in patients undergoing elective bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy. The risk of such complications is increased if adhesions or other intraabdominal pathology are present.
The impact of BSO on surgical morbidity is controversial. This may depend somewhat upon surgical route. For hysterectomy performed via laparotomy or laparoscopy, BSO does not appreciably increase the complexity of the procedure. By contrast, when BSO is combined with vaginal hysterectomy, the procedure is potentially more difficult. The degree of difficulty depends upon the extent of descensus of the ovaries and the extent to which the ovaries can be brought into the narrow surgical field. This is consistent with the findings of a study of over two million patients in the United States who underwent hysterectomy for benign indications from 1998 to 2006 [47]. There was an increase in complications when BSO was performed in patients undergoing vaginal hysterectomy (odds ratio [OR] 1.12, 95% CI 1.08-1.17), but not for those who had an abdominal (OR 0.91, 95% CI 0.89-0.94) or laparoscopic hysterectomy (OR 0.89, 95% CI 0.83-0.94). (See "Abdominal hysterectomy", section on 'Adnexal conservation or removal' and "Vaginal hysterectomy", section on 'Adnexal evaluation and surgery'.)
By contrast, an increase in morbidity with BSO was found in another study of over nine million patients who had a hysterectomy performed between 1979 and 2004 identified via the United States National Hospital Discharge Survey database. Most were abdominal hysterectomies (84 percent); individual rates of other surgical routes were not given [48]. A study population with a predominantly abdominal surgical route is no longer representative of current practice. A better surrogate, perhaps, is data from a 2019 Cochrane review that evaluated risk of hysterectomy versus risks of hysterectomy plus elective salpingectomy. No differences in complication rates were found [49], although rates of adverse events were quite low (blood loss, short-term postoperative surgical complications, operative time, and hospital length of stay were assessed).
The available data do not take into consideration whether the oophorectomy was elective or indicated. Some indications for oophorectomy may contribute to surgical morbidity (eg, pelvic adhesions, large adnexal mass). Further study is needed to evaluate whether elective BSO impacts surgical morbidity.
Long-term health risks — Accumulating evidence indicates that surgical removal of the ovaries may have serious long-term health consequences [25-29,50-56]. It appears that risks are greater for patients who are younger at the time of oophorectomy and did not take estrogen therapy [29,50-52,55,56].
All-cause mortality — The available evidence suggests that bilateral oophorectomy at younger age is associated with increased all-cause mortality, especially among patients who do not take estrogen therapy. Questions remain regarding the potential mechanism of this effect, but evidence is suggestive that hypoestrogenism may be an important factor leading to endothelial dysfunction.
The Nurses' Health Study (NHS) found that patients who underwent bilateral oophorectomy had a significantly increased risk of death from all causes compared with those who conserved their ovaries (16.8 versus 13.3 percent, hazard ratio [HR] 1.13, 95% CI 1.06-1.21) (see 'Studies regarding elective oophorectomy' above). This can also be expressed as one additional death over a period of 24 years for every 24 patients who undergo bilateral oophorectomy at time of hysterectomy.
The etiology of the increase in all-cause mortality with oophorectomy in the NHS is unknown, but among patients younger than 50 years, the increase in risk following oophorectomy was significantly higher for those who never used estrogen therapy (HR 1.41, 95% CI 1.04-1.92) than those who had ever used, or were currently, using estrogen therapy (HR 1.05, 95% CI 0.94-1.17) [26]. Among all patients, oophorectomy was associated with a significant increase in death due to lung cancer (HR 1.29, 95% CI 1.04-1.61), and colorectal cancer (HR 1.49, 95% CI 1.02-2.18).
As in the NHS, younger patients in the Mayo Cohort Oophorectomy and Aging Study who underwent prophylactic BSO had an increased all-cause mortality risk (HR 1.67, 95% CI 1.16-2.40) [29]. Supporting the finding of decreased all-cause mortality with ovarian conservation is a nationwide United Kingdom study, a retrospective analysis of the English Hospital Episode Statistics database linked to national death registries that included 113,679 patients ages 35 to 45 who had hysterectomy for benign conditions with BSO versus conservation of at least one ovary (HR 0.64, 95% CI 0.55-0.73) [28].
The retrospective nationwide United Kingdom study supported the NHS findings; conservation of at least one ovary in patients ages 35 to 45 who had hysterectomy for benign conditions was associated with a lower all-cause risk (HR 0.64, 95% CI 0.55-0.73) [28].
Elective and indicated oophorectomies were analyzed separately in only one study, the Mayo Cohort Study of Oophorectomy and Aging [29,30] (see 'Studies regarding elective oophorectomy' above). A significant increase in all-cause mortality compared with referent patients without oophorectomy was found only in those in whom the oophorectomy was indicated due to a benign tumor or inflammation. The causes of death were not reported. The risk of death was significantly increased in patients who underwent prophylactic oophorectomy compared with no oophorectomy only in those who were younger than age 45 years and did not use subsequent estrogen therapy (29 versus 26 percent). The study lacked sufficient statistical power to detect a difference in outcome in other patients who underwent prophylactic oophorectomy. Further study of the distinction between indicated and elective oophorectomies is needed. (See 'Indications for oophorectomy' above.)
In contrast to findings from the NHS, the United Kingdom study, and the Mayo Cohort Study of Oophorectomy and Aging, the Women's Health Initiative (WHI) Observational Study found no increase in mortality in patients who underwent hysterectomy with bilateral oophorectomy compared with ovarian conservation, overall (797 versus 791 per 100,000 person-years, HR 0.98, 95% CI 0.87-1.10) or for any age group subset [27]. A discussion of study limitations can be found above. (See 'Studies regarding elective oophorectomy' above.)
Cardiovascular disease and stroke — The available evidence suggests that both BSO at a younger age and premature menopause are associated with an increased risk of cardiovascular disease (CVD) and stroke [26,28,55,57-61]. Data suggest that estrogen therapy may mitigate adverse cardiovascular effects in this patient population [25,52,58,60]. The relationship between postmenopausal hormone therapy and CVD is discussed in detail separately. (See "Menopausal hormone therapy and cardiovascular risk".)
The associations between CVD, oophorectomy, and natural menopause are demonstrated by the following representative studies:
●Premature surgical menopause – Premature surgical menopause appears to be associated with a small increased risk of cardiovascular events compared with both premature natural and natural menopause. A United Kingdom cohort study of over 140,000 postmenopausal patients reported, after controlling for cardiovascular risk factors and ever-use of hormone therapy, cardiovascular event incidences of 5.7, 8.8, and 11.7 per 1000 person-years for natural, premature natural, and premature surgical menopause groups, respectively (n = 5415, 292, and 49) [58]. We find this information useful for more accurately counseling patients who experience premature surgical menopause and offer them immediate and continued estrogen therapy up to age 50 years. (See 'Estrogen therapy after oophorectomy' below.)
●Premature natural menopause – Premature natural menopause (menopause prior to the age of 40 years) is associated with an increased risk of cardiovascular events compared with natural menopause, but the absolute risk remains low. The above United Kingdom cohort study of over 140,000 postmenopausal patients reported a small but increased risk of cardiovascular events in patients with natural premature menopause compared with patients experiencing natural menopause at age ≥40 years [58]. After controlling for cardiovascular risk factors and ever-use of menopausal hormone therapy, the incidence of cardiovascular events was 5.7 and 8.8 per 1000 person-years for natural and premature natural menopause, respectively (n = 5415 and 292). In a post hoc analysis, CVD risk for patients with premature natural menopause and patients with BSO at age <40 were similar. We find this information useful in counseling patients who experience early natural menopause and recommend consistent and ongoing hormone therapy up to age 50. (See 'Estrogen therapy after oophorectomy' below.)
By contrast, the WHI Observational Study reported no significant association between oophorectomy (study population age at BSO: <40, 22 percent; 40 to 49, 47 percent; ≥50, 31 percent) and coronary heart disease. Lack of increased risk for CVD with BSO could be explained by the following: Nearly 80 percent of patients were >40 at the time of BSO, 66 percent were current users of estrogen therapy, and over 60 percent had used estrogen therapy for >5 years [27]. A discussion of study limitations can be found above. Our approach is to use these studies to counsel patients about the importance of decreasing risks of CVD by taking estrogen therapy when deciding whether or not to remove ovaries, particularly at younger ages. (See 'Studies regarding elective oophorectomy' above.)
●Early natural menopause – The impact of early natural menopause (menopause by age 45 years, an arbitrary cut-off used in many studies) is less clear. The 2019 cohort study included both smokers and nonsmokers, controlled for smoking status, and did not report significant increases in CVD among patients with early natural menopause (ages 40 to 45) for most outcomes [58]. In a 2016 meta-analysis of 32 studies including 310,000 patients, menopause before age 45 was associated with an elevated CVD incidence compared with menopause at 45 years or older (relative risk 1.56, 95% CI 1.08-2.26) [60]. Earlier studies reported that CVD risk with earlier menopause was limited to current smokers [62], while a 2005 study reported the effect in patients who never smoked [63]. (See "Overview of atherosclerotic cardiovascular risk factors in females", section on 'Early menopause'.)
●Oophorectomy during menopause transition – There may not be an increased risk for CVD among patients who undergo BSO in the menopause transition. The Study of Women's Health Across the Nation, a prospective cohort study of over 3000 premenopausal patients from diverse ethnic backgrounds, followed 42- to 52-year-olds for up to 11 years. By 2008, 1769 had become menopausal, 77 had hysterectomy, and 106 had hysterectomy with BSO. Patients were followed annually for changes in risks for CVD for an average of 4.7±2.3 years after the final menstrual period or surgery [64]. No differences between groups were observed in annual changes in CVD risk factors: lipids, insulin resistance, blood pressure, hemostatic, and inflammatory factors.
In the United Kingdom cohort study, significant differences in CVD outcomes were not observed when patients with oophorectomy in the menopause transition were compared with those who experienced natural menopause [58].
●Potential benefit of hormone therapy – Studies suggest benefit of hormone therapy on cardiovascular outcomes for patients who had premature surgical or natural menopause (ie, menopause onset before age 40 years). In a post hoc analysis of the large United Kingdom cohort that evaluated whether estrogen therapy for five or more years might mitigate risk of cardiovascular events, the HR approached 1, which suggested benefit for patients who consistently used estrogen therapy following premature surgical menopause or premature natural menopause [58]. The NHS found a significant increase in CVD (HR 1.19, 95% CI 1.01-1.39) and a nonsignificant increase in coronary heart disease (HR 1.23, 95% CI 1.00-1.52) among patients younger than 50 years who had had BSO as compared with those over 50 [26]. Among patients who had BSO and were younger than 50 years and never used estrogen therapy, the risk was higher (HR 1.60, 95% CI 0.68-3.74) versus those who had ever used or were currently using estrogen therapy (HR 1.00, 95% CI 0.76-1.33).
Similarly, among younger patients in the Mayo Cohort Oophorectomy and Aging Study, those who underwent BSO and were not treated with estrogen from the time of BSO through age 45 years had an increased cardiovascular mortality risk (HR 1.84, 95% CI 1.27-2.68), while those who were treated with estrogen therapy were not found to have a significantly increased risk (HR 0.65, 95% CI 0.30-1.41), although this analysis had insufficient statistical power [52].
●Premature menopause and stroke – The United Kingdom cohort study reported the risk for ischemic stroke was 50 percent greater in patients with premature menopause as compared with those with natural menopause (HR 1.50, 95% CI 1.01-2.25) [58]. A meta-analysis of 32 studies also found an increased risk for stroke for patients <45 at the time of menopause (compared with patients ≥45, HR 1.23, 95% CI 0.98-1.53) for overall stroke. Others have not demonstrated an association [65,66].
Chronic kidney disease — Oophorectomy prior to age 50 may be associated with an increased risk of chronic kidney disease (CKD). A single study published by the Mayo Clinic Cohort Study of Oophorectomy and Aging (MOA-2) showed a higher risk of CKD among patients who underwent oophorectomy prior to age 50 compared with those who did not (adjusted HR [aHR] 1.42, 95% CI 1.14-1.77); the risk was highest in patients ≤45 years (aHR 1.59, 95% CI 1.15-2.19) [67]. Hormone replacement therapy seemed to mitigate some of this risk; in patients ≤45 years, the aHR was lower in those who took hormone replacement therapy (HR 1.52) compared with those who did not (HR 2.07).
It is hypothesized that the potential increased risk for CKD associated with young age at bilateral oophorectomy is due to endothelial dysfunction, glomerulosclerosis, and increased glomerular permeability.
Cognitive function and neurologic disease — Oophorectomy prior to menopause appears to be associated with an increased risk of cognitive impairment or dementia, as well as parkinsonism [50,56,68-72]. Estrogen therapy may be neuroprotective in these patients. (See "Estrogen and cognitive function", section on 'Timing of exposure' and "Menopausal hormone therapy: Benefits and risks", section on 'Cognitive function and dementia'.)
This was illustrated in the MOA [56,68,69]. Among patients who underwent bilateral oophorectomy before menopause compared with those who did not undergo oophorectomy, a significant increase in the risk of cognitive impairment or dementia was restricted to those who were younger than 48 years old at time of surgery and who did not take estrogen therapy from time of surgery through age 50 years (HR 1.89, 95% CI 1.27-2.83).
Small observational studies have shown a significant decrease in specific cognitive functions after bilateral oophorectomy, including verbal fluency, verbal memory, procedural learning, and some other executive functions [50,70]. Neurocognitive performance was worse when oophorectomy occurred at younger ages and worse with a greater decline in estradiol levels, but it was better when hormone therapy was initiated after oophorectomy. The extent to which observed improvements in neurocognitive performance with estrogen therapy might be attributable to improvements in sleep and relief of hot flashes versus direct effects on the brain has been debated [70].
In the MOA, patients who underwent bilateral oophorectomy before the onset of menopause had an increased risk of parkinsonism compared with no oophorectomy (2.6 versus 1.2 percent), and the risk increased with younger age at oophorectomy [69,71]. An increase in the risk of Parkinson's disease was also found, but this did not reach statistical significance. In a subsequent cohort study including almost 5500 patients (median age 45 years), patients with versus without a history of oophorectomy also had higher rates of examination or medical record-confirmed parkinsonism (HR 1.59; 95% CI 1.02-2.46) [72]. While rates of Parkinson's disease were similar between groups overall, rates were higher in those with oophorectomy prior to age 43 years (HR 5, 95% CI 1.1-22.7).
Depression and anxiety — Some data suggest that early bilateral oophorectomy at the time of hysterectomy is associated with an increased risk of developing depression or anxiety [50,56,73,74].
The MOA reported that patients who had bilateral oophorectomy compared with those who did not had a significant increase in the onset of symptoms of depression (as diagnosed by a physician, 11 versus 7 percent) or anxiety (7 versus 3 percent) [50]. The median time from oophorectomy to the onset of symptoms of depression or anxiety was approximately 14 years, but differences in the rates of occurrence of anxiety and depression were observed within three years following hysterectomy, and persisted throughout more than 30 years of follow-up.
The Study of Women's Health Across the Nation compared risk of depression and anxiety among patients who had hysterectomy with ovarian conservation (n = 76) versus those who had hysterectomy with bilateral oophorectomy (n = 101). For all subjects, depressive and anxiety symptoms decreased in the years after final menstrual period or surgery [74].
Data from shorter-term studies have been inconsistent regarding the effect of bilateral oophorectomy on psychological well-being [75,76].
Glaucoma — Neuroprotective effects of estrogen on the optic nerve and a decreased risk of glaucoma, the second leading cause of blindness world-wide, have been described [53,54]. (See "Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis".)
The MOA reported that patients who had bilateral oophorectomy before the age of 43 years compared with those who did not have a significant increase in open-angle-glaucoma (as identified by diagnostic codes and confirmed in a subset chart validation study). The risk (aHR 1.60, 95% CI 1.15-2.23) was not ameliorated in patients who took estrogen, although numbers were small [53]. In the NHS, glaucoma risk was 50 percent lower in patients who underwent menopause at 54 years or older, compared with those under 54 years [54].
Sexual dysfunction — Studies report negative sexual outcomes after oophorectomy in premenopausal patients not treated with hormones [77].
Sexual function outcomes have been evaluated by several categories, including libido, arousal, satisfaction with sex, and overall sexual outcome. Three studies looked at sexual desire [78-80]. Two studies showed a difference between conservation of ovaries and BSO, whereas a smaller study showed no difference. A prospective cohort study found that hysterectomy was associated with extreme negative impacts on sexual function, using endometrial ablation as a control. Hysterectomy with BSO was associated with more severe effects than hysterectomy alone on loss of libido (with BSO, 1.8-fold higher odds and without BSO, 1.4-fold higher) and difficult sexual arousal (1.7 and 1.4) [79]. Another prospective study provided the best evidence regarding orgasm and reported a 2.7-fold higher rate of not experiencing orgasm among patients who had hysterectomy with BSO compared with hysterectomy with ovarian conservation [78]. Studies that looked at symptoms of vaginal dryness [78,79] and satisfaction with sex [80] showed no difference between groups (moderate quality). Finally, in a measure of composite sexual outcome (combined frequency of sexual activities, dyspareunia, and libido), hysterectomy alone or with unilateral salpingo-oophorectomy was associated with less deterioration in sexual function than hysterectomy with BSO [78].
Adverse effects of bilateral oophorectomy can involve several different domains of sexual function, including libido, arousal, and orgasm [73]. In a survey of European patients with no known increased risk of cancer, those who underwent bilateral oophorectomy were twice as likely to have hypoactive sexual desire symptoms compared with patients who were premenopausal or had gone through natural menopause [81].
Greater impairment of sexual function may be associated with surgical versus natural menopause, particularly in patients less than 50 years old, since only surgical menopause is associated with an abrupt decrease in androgen output. In a cross-sectional study of over 30,000 patients, surgical, but not natural, menopause was associated with orgasm problems, and the decrease in arousal was greater in patients after surgical menopause [82]. Similarly, in a two-year prospective study of over 1000 patients who had a hysterectomy (most were under 50 years of age), those who had bilateral oophorectomy reported a threefold increased risk of anorgasmia postoperatively, compared with patients who had their ovaries preserved [78]. On the other hand, this result was not observed in a subsequent prospective study in which sexuality was unaltered postoperatively in patients following hysterectomy with bilateral oophorectomy compared with hysterectomy only, although most patients were perimenopausal and most were treated with hormone therapy [83]. (See "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation", section on 'Age and menopause'.)
Other studies have found that overall sexual function is unaltered after oophorectomy, or that alterations were explained by preoperative sexual function, indications for surgery, severity of symptoms, and personality traits, rather than by the oophorectomy itself, and the majority of patients in these studies were in the menopause transition or were postmenopausal, and many were using hormone therapy [84-86].
Osteoporosis — Menopause is a known risk factor for osteoporosis. Among patients in the Mayo Clinic Cohort of Oophorectomy and Aging who were postmenopausal at the time of surgery, there was a significant increase in the risk of any osteoporotic fracture (moderate trauma fractures of the hip, spine, or distal forearm) as compared with expected rates (standardized incidence ratio [SIR] 1.54, 95% CI 1.29-1.82), but almost as large an increase in fractures at other sites (SIR 1.35, 95% CI 1.13-1.59) [87]. Likewise, patients who were premenopausal at the time of surgery had an increased risk of distal forearm (SIR 1.4, 95% CI 1.0-2.0) and vertebral fractures (SIR 1.9, 95% CI 1.3-2.8) but not hip fracture (SIR 1.1, 95% CI 0.6-1.9) [31].
However, oophorectomy at the time of hysterectomy was not found to be associated with hip fracture in either the NHS or the WHI Observational Study [25,27]. It is important to note the age of participants in these studies was overall lower than the peak age for osteoporotic fractures. (See 'Studies regarding elective oophorectomy' above.)
CLINICAL DECISION MAKING — The decision regarding elective oophorectomy at time of hysterectomy for benign indications relies on an understanding of genetic risk factors for cancer. The approach to decisions must include comprehensive counseling regarding risks and benefits and shared decision making between the clinician and patient.
The first step is to determine whether the choice regarding oophorectomy is truly elective (see 'Indications for oophorectomy' above). All patients planning hysterectomy should be assessed for risk factors for ovarian and breast cancer. In addition, an appropriate evaluation for extrauterine pelvic pathology should be performed. Strategies for cancer risk reduction in patients at high risk of ovarian cancer due to hereditary ovarian and breast cancer syndromes are discussed separately. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer", section on 'Efficacy of cancer risk reduction' and "Cancer risks and management of BRCA1/2 carriers without cancer".)
Bilateral oophorectomy is associated with a small absolute cancer risk reduction for patients who are at an average risk of ovarian or breast cancer. Ovarian cancer is not a common disease and hysterectomy itself provides a small preventive effect. Removal of the fallopian tube may provide added risk reduction. Some data suggest an association between oophorectomy and decreased risk of breast cancer in patients who are younger than 45 years, but no decrease in breast cancer mortality has been found. (See 'Ovarian cancer risk reduction' above and 'Breast cancer risk reduction' above.)
There are conflicting data on long-term health effects of elective oophorectomy beyond ovarian and breast cancer risk reduction. The best available data are from observational studies, but not all studies are in agreement. Given the current evidence, elective oophorectomy may be associated with an increase in long-term risks of all-cause mortality and cardiovascular disease, particularly in patients who are younger than 45 and perhaps up to 54 years at the time of surgery (see 'All-cause mortality' above and 'Cardiovascular disease and stroke' above). Chronic kidney disease, cognitive impairment, parkinsonism, psychiatric symptoms, sexual dysfunction, and osteoporosis are additional risks. (See 'Cognitive function and neurologic disease' above and 'Depression and anxiety' above and 'Sexual dysfunction' above and 'Osteoporosis' above.)
In the short term, premenopausal patients who undergo bilateral oophorectomy will experience the abrupt onset of menopause and will typically have bothersome menopausal symptoms (eg, hot flashes, sleep disturbance, and mood changes). These symptoms may be treated with postmenopausal estrogen therapy; significant risks of therapy have not been demonstrated in premenopausal patients. Withholding estrogen therapy from young patients who experience premature or early menopause due to oophorectomy, however, may, on the other hand, pose significant risks, based on the evidence presented here. (See "Menopausal hormone therapy: Benefits and risks".)
For patients who have already experienced natural menopause, elective bilateral oophorectomy may be health neutral. Although, a decision analysis based upon a comprehensive review of observational data concluded that ovarian conservation at time of benign hysterectomy until age 65 years benefits long-term survival, and that the risks and benefits of elective oophorectomy approximate each other after age 65 years [88].
Given these considerations and the available data, for most patients who undergo hysterectomy for benign indications in the absence of ovarian pathology or a familial cancer syndrome, we suggest ovarian conservation and discussion regarding removal of the fallopian tubes. Oophorectomy is reasonable for patients who place a higher priority on ovarian cancer prevention than on other long-term health risks, particularly those who are 51 years old or older.
The decision regarding salpingo-oophorectomy is more difficult for patients who have some risk factors for ovarian cancer (table 3), but who do not have a hereditary cancer syndrome. Ovarian cancer risk assessment tools have been proposed, but are not well validated. As an example, one case control study found a 4 percent lifetime increased risk of ovarian cancer in patients with five or more of the following risk factors: Jewish ethnicity, less than one year of oral contraceptive use, nulliparity, no breastfeeding, no tubal ligation, painful periods or endometriosis, polycystic ovarian syndrome or obesity, and talc use [89]. Counseling of such patients believed to be at intermediate risk of ovarian cancer must be individualized, and should include a full discussion of all of the advantages and disadvantages of elective oophorectomy versus elective salpingectomy versus elective salpingo-oophorectomy. (See 'Ovarian cancer risk reduction' above.)
ESTROGEN THERAPY AFTER OOPHORECTOMY — Patients experiencing premature or early menopause due to bilateral oophorectomy at the time of hysterectomy are different from those who reach menopause at the median age of 51 years, and data regarding the use of hormone therapy in naturally menopausal patients should not be extrapolated to those who have surgical menopause [90-93]. Observational data consistently indicate that several of the serious long-term health consequences of bilateral oophorectomy can be ameliorated by taking estrogen therapy until at least 60 years of age [26,29,52,56,68]. Patients who are treated with hormone therapy after hysterectomy with bilateral oophorectomy require only estrogen therapy since a progestogen for endometrial protection is not needed. For patients under the age of 45, we prescribe either transdermal estradiol (100 mcg daily) or an estradiol vaginal ring (100 mcg daily), which is roughly equivalent to 2 mg daily of oral micronized estradiol and based on the average daily production of estradiol by the premenopausal ovary. These doses are higher than those recommended for postmenopausal patients and are similar to the doses recommended for patients with premature ovarian insufficiency. (See 'Risks of elective oophorectomy' above and "Treatment of menopausal symptoms with hormone therapy", section on 'Surgical menopause' and "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Importance of estrogen therapy'.)
Data from the Women's Health Initiative (WHI) are informative. Use of conjugated equine estrogen (CEE) alone is not associated with the risks seen in users of CEE plus progestin therapy [94]. Importantly, in the WHI Estrogen-Alone Trial that evaluated patients ages 50 to 79 with prior hysterectomy, random assignment to CEE for a median of 7.2 years was associated with a similar pattern of benefits and risks in patients with and without bilateral salpingo-oophorectomy (BSO) [95]. However, younger age at randomization strongly reduced all-cause mortality risk, particularly among patients with BSO. Among patients with prior hysterectomy who were randomly assigned to CEE alone or placebo, the risk of all-cause mortality was lower for those between the ages of 50 and 59 who had BSO compared with patients without but did not differ among those in other age groups (patients ages 50 to 59 years: hazard ratio [HR] 0.68, 95% CI 0.48-0.96; patients ages 60 to 69: HR 0.88, 95% CI 0.74-1.05; patients ages 70 to 79: HR 1.02, 95% CI 0.86-1.21). This differential effect based on patient age at the initiation of hormone use is referred to as the "timing effect" and highlights the need for individualized care when discussing initiation of hormone therapy with patients who have had elective oophorectomy.
●(See "Menopausal hormone therapy and cardiovascular risk", section on 'Timing of exposure'.)
Discussions of hormone therapy types, initiation, and use are presented in detail separately. Following bilateral oophorectomy, some clinicians also treat patients with androgen therapy for sexual dysfunction; other indications for androgens in this population are not well established, and long-term safety data are lacking [96].
●(See "Preparations for menopausal hormone therapy".)
●(See "Treatment of menopausal symptoms with hormone therapy".)
●(See "Overview of sexual dysfunction in females: Management", section on 'Androgens'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gynecologic surgery".)
SUMMARY AND RECOMMENDATIONS
●Terminology – Elective oophorectomy refers to the removal of the ovaries in a patient who has no known indication for this procedure (eg, ovarian pathology, hereditary ovarian cancer syndrome). Risk-reducing salpingo-oophorectomy refers to the removal of the tubes and ovaries in a patient at high risk of ovarian or breast cancer due to a known gene mutation. (See 'Terminology' above.)
●Benefits
•Oophorectomy is associated with a reduction in the risk of ovarian cancer, although the age at which the benefit occurs is uncertain. (See 'Ovarian cancer risk reduction' above.)
•Data suggest that breast cancer risk is reduced in patients <47.5 years at oophorectomy; this reduction may extend to age 60 years. (See 'Breast cancer risk reduction' above.)
●Long-term health risks
•Oophorectomy appears to increase long-term mortality and cardiovascular risk in patients under the age of 60 who do not take estrogen therapy. (See 'Long-term health risks' above.)
•Oophorectomy without estrogen therapy, particularly before menopause, also has potential deleterious effects on the risk for chronic kidney disease, cognitive decline, parkinsonism, depression and anxiety, glaucoma, sexual dysfunction, and osteoporotic fractures. (See 'Long-term health risks' above.)
●Counseling
•For most patients who undergo hysterectomy for benign indications, in the absence of ovarian pathology or a familial cancer syndrome, we suggest ovarian conservation (Grade 2C). We also recommend that there be a discussion about elective salpingectomy with ovarian preservation. Oophorectomy is reasonable for patients who are 51 years of age or older who place a higher priority on ovarian or breast cancer prevention than on the potential risks of mortality and cardiovascular disease that have been suggested by some studies. For patients who elect oophorectomy, estrogen therapy is recommended until at least age 60. (See 'Clinical decision making' above and "Opportunistic salpingectomy for ovarian, fallopian tube, and peritoneal carcinoma risk reduction".)
•Counseling of patients with risk factors for ovarian cancer (table 3), but who do not have a hereditary cancer syndrome, must be individualized. (See 'Clinical decision making' above.)
●Role of estrogen therapy – Patients who undergo oophorectomy, inducing premature (before age 40 years) or early (before age 45 years) menopause, are likely to benefit from estrogen therapy until age 60. The dose required for these patients is higher than what is used for patients >50 years; we prescribe either transdermal estradiol (100 mcg daily) or an estradiol vaginal ring (100 mcg daily). (See 'Estrogen therapy after oophorectomy' above and "Management of primary ovarian insufficiency (premature ovarian failure)".)
