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Ovarian conservation vs removal at the time of benign hysterectomy
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Ovarian conservation vs removal at the time of benign hysterectomy Marisa R. Adelman, MD; Howard T. Sharp, MD
Introduction Oophorectomy at the time of hysterectomy occurs at a rate of 40-50% in the United States.1-5 Commonly cited rationales for bilateral salpingooophorectomy (BSO) are prevention of ovarian cancer and decreased risk of subsequent surgery. The sequelae of BSO include increased mortality due to all causes, cardiovascular disease, deficits of cognitive and sexual functioning, and osteoporosis. Historically, hormone therapy (HT) has been used to mitigate the effects of estrogen deficiency. In a study of HT compliance, 3% of women discontinued HT by 2 years, 20% by 5 years, and 67% by 10 years.6 The Women’s Health Initiative (WHI) observed a discontinuation rate of 42% at an average of 5.2 years of follow-up.7 Although the primary objective of the WHI was to evaluate whether HT had favorable effects on coronary heart disease (CHD),7,8 its main effect was to change the prescribing practice of HT. Importantly, the postmenopausal ovary appears to be an ongoing site of testosterone production. A decline in serum androgens is observed throughout the reproductive years, with minimal change in the midlife, and a slight increase in the seventh decade. While natural menopause does not seem to affect serum androgen levels, oophorectomy results in significantly lower levels of total and free testosterone.9 The
From the Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT. Received May 11, 2017; revised July 14, 2017; accepted July 31, 2017. The authors report no conflict of interest. Corresponding author: Marisa R. Adelman, MD. [email protected] 0002-9378/$36.00 ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.07.037
Over the last 2 decades, the rate of oophorectomy at the time of hysterectomy in the United States has consistently been between 40-50%. A decline in hormone use has been observed since the release of the principal results of the Women’s Health Initiative. Oophorectomy appears to be associated with an increased risk of coronary heart disease, as well as deleterious effects on overall mortality, cognitive functioning, and sexual functioning. Estrogen deficiency from surgical menopause is associated with bone mineral density loss and increased fracture risk. While hormone therapy may mitigate these effects, at no age does there appear to be a survival benefit associated with oophorectomy. Reduction of ovarian cancer risk may be accomplished with salpingectomy at the time of hysterectomy. Key words: morbidity, mortality, oophorectomy, ovarian cancer, ovarian conservation
postmenopausal ovary is therefore a source of androgens in older women, and provides precursors for estrogen metabolism. This is particularly relevant to bone health, cardiovascular health, sexual functioning, and cognitive functioning. In this article, we consider recent trends in oophorectomy, the risks and benefits, the role of HT, and alternatives for risk reduction of ovarian cancer.
Trends in oophorectomy Multiple large population-based databases have examined the overall rate of oophorectomy at the time of hysterectomy in the United States. The percentage has been consistently in the mid-40s (43.7%-46.7%).1-5 After the release of the initial WHI results in 2002, an acute decline in BSO rate was noted.3,4,10 The decline was observed in all age groups, but most notably in women aged 45-49 years.10 While the age-adjusted risk of oophorectomy with hysterectomy declined in women 50 years of age, the risk for women age >50 years increased.11 Age has repeatedly been identified as an independent risk factor for elective oophorectomy during hysterectomy, starting as young as 45 years. Lowder et al11 observed an odds ratio of 11.4 (95% confidence interval [CI],
10.2e12.7) for oophorectomy at age 45-49 years, and 17.7 (95% CI, 15.6e20.2) at age 50-54 years, when compared to women <35 years old. Similarly, Asante et al10 observed the highest rates of elective oophorectomy in women aged 45-49 years, followed by women aged 50-54 years. In a study by Jacoby et al,1 the odds of undergoing BSO increased approximately 30% with each year of advancing age between 40-49 years. Despite the recent increase in ovarian conservation for women aged 45-49 years, the rate of oophorectomy in this age group is approximately 60%.1,5 The rate of oophorectomy in women age of >55 years is 65-75%.1,3,5 While age appears to play the most prominent role in the decision to remove or retain ovaries, several clinical and demographic variables have also been identified. A personal history of breast cancer or a family history of breast or ovarian cancer is associated with elective oophorectomy during hysterectomy, even when genetic susceptibility mutations are not identified.2,4
All-cause mortality In 2005, Parker et al12 published a Markov decision analysis to estimate the optimal strategy for maximizing survival in women at average risk of ovarian cancer. The risks and benefits of
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TABLE 1
All-cause mortality and oophorectomy Author
Deleterious effect of BSO
Cohort
Major findings
Ossewaard et al, 2005
Dutch breast cancer screening cohort
Yes
2% Decrease in total mortality per year of delayed menopause
Rocca et al,14 2006
Mayo Clinic Cohort Study of Oophorectomy and Aging
Yes
Increased risk of mortality with bilateral oophorectomy age <45 y (HR, 1.67; 95% CI, 1.16e2.40)
Parker et al,15 2009 Parker et al,16 2013
Nurses’ Health Study
Yes
Oophorectomy associated with increased risk of all-cause death (HR, 1.13; 95% CI, 1.06e1.21) Even higher risk of all-cause death observed in women who underwent oophorectomy age <50 y, and never used estrogen therapy (HR, 1.41; 95% CI, 1.04e1.92)
Jacoby et al,19 2011
Women’s Health Initiative
No
BSO not associated with increased risk of death in multivariate analysis (HR, 0.98; 95% CI, 0.87e1.10) BSO not associated with increased risk of death in subset of women who never used HT (HR, 0.99; 95% CI, 0.80e1.23)
Gierach et al,17 2014
Breast Cancer Detection Demonstration Project
Yes
Women who underwent BSO by age 35 y had increased risk of death from any cause (HR, 1.20; 95% CI, 1.08e1.34), which progressively decreased when surgery was performed later in life By age 50 y, risk was no longer increased (HR, 1.05; 95% CI, 0.99e1.10)
Mytton et al,18 2017
English Healthcare Registries
Yes
Ovarian conservation was associated with significantly lower rate of all-cause death (HR, 0.64; 95% CI, 0.55e0.73)
13
BSO, bilateral salpingo-oophorectomy; CI, confidence interval; HR, hazard ratio; HT, hormone therapy. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
oophorectomy at the time of surgery for benign gynecologic disease were considered, and included overall mortality, as well as mortality from CHD, hip fracture, stroke, ovarian cancer, and breast cancer. The highest rates of survival were observed in the ovarian conservation cohorts, either with or without estrogen therapy (ET), and were measured in survival to age 80 years. Oophorectomy with ET was associated with a comparable survival (62.15%) to ovarian conservation with ET (62.75%), while oophorectomy without ET was associated with a much lower proportion of survival (53.88%). Similar results have been observed in a variety of large cohort studies (Table 1), including a Dutch breast cancer screening cohort,13 the Mayo Clinic Cohort Study of Oophorectomy and Aging,14 the Nurses’ Health Study,15,16 the Breast Cancer Detection
Demonstration Project,17 as well as a retrospective analysis of English national databases.18 An increased risk of death from any cause was particularly apparent in women who underwent oophorectomy age <45-50 years, and never used ET. At no age was there an overall survival benefit associated with bilateral oophorectomy at the time of hysterectomy. The only large prospective observational cohort to not demonstrate a deleterious effect of BSO on mortality was the WHI.19 In multivariate analysis, BSO was not associated with an increased risk of overall mortality. However, the differences in study demographics should be taken into consideration when this cohort is used for comparison. The average age at the time of enrollment was 63 years, average follow-up was 7.6 years, and 78.6% of the cohort were past or current users of
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HT. The relatively older age at the time of enrollment, shorter follow-up, and prevalence of HT use may account for the absence of any interaction between BSO and mortality that was observed in the other studies. In summary, the vast majority of the literature supports a deleterious effect of oophorectomy on overall mortality, particularly when performed at age <50 years. ET appears to mitigate the increase in overall mortality associated with oophorectomy, but at no age was a survival benefit shown. Based on Markov modeling, ovarian conservation may even confer a long-term survival benefit until the age of 65 years.12
Cancer risk and mortality It has been estimated that 1000 cases of ovarian cancer could be prevented annually, if every woman age >40 years underwent BSO at the time of
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ajog.org hysterectomy.20 This estimate has frequently been taken out of context, as the long-term benefit is predicated on the assumption that oophorectomized women will be completely compliant with estrogen replacement therapy. A Markov analysis by Speroff et al21 identified a shorter life expectancy in women who undergo oophorectomy age <45 years, with typical HT rates. The data on hysterectomy, oophorectomy, and all-cause cancer risk as well as mortality show mixed conclusions with mostly marginal magnitudes of effect16,22,23 (Table 2). Hysterectomy with oophorectomy, as would be expected, has a dramatic impact on ovarian cancer risk reduction16,19,24 but there also appears to be benefit to hysterectomy alone. The data are mixed on colorectal cancer risk relative to oophorectomy,16,18,19,23,25,26 as well as lung cancer risk.16,18,19,23,27 Oophorectomy prior to menopause has been associated with a lower risk of death from breast cancer15,16,28 in several studies, and may even affect some women’s attitude towards oophorectomy at the time of hysterectomy. Interestingly, retrospective analysis by Mytton et al18 of all English women aged 35-45 years undergoing hysterectomy for benign indications found that there was an increased incidence of breast cancer with ovarian conservation, but the rate of death from breast cancer was actually significantly lower (hazard ratio [HR], 0.61; 95% CI, 0.39e0.94). The authors comment that with longer follow-up, it is possible that the rate of death from breast cancer may eventually rise. This study included 113,678 patients over a 10-year study period, and represents the largest study to examine the relationship between oophorectomy and adverse outcomes. In this study, the rate of death from any cancer was significantly lower in the ovarian conservation group (HR, 0.54; 95% CI, 0.45e0.65). The fact that BSO is associated with a lower incidence of breast and ovarian cancer may be offset by the higher rate of death from all cancer, and should be included in the discussion of women considering BSO for the purpose of cancer risk reduction.
CHD risk and mortality The Nurses’ Health Study cohort demonstrated that women who had undergone bilateral oophorectomy, and had never taken estrogen after menopause, had an increased risk of CHD29 (Table 3). The use of ET in the early postmenopausal period of surgically menopausal women, however, appeared to eliminate the increased risk, while the use of ET after natural menopause had no effect on risk. After 24 years of followup data from the Nurses’ Health Study, oophorectomy is still associated with an increased risk of CHD at all ages of oophorectomy (HR, 1.17; 95% CI, 1.02e1.35), but particularly for women <45 years old (HR, 1.26; 95% CI, 1.04e1.54).15 The risk was further illustrated in women who underwent oophorectomy at age <50 years, but who never used ET (HR, 1.98; 95% CI, 1.18e3.32). There have been several other large studies that associated CHD with hysterectomy and oophorectomy, including the Mayo Clinic Cohort Study of Oophorectomy and Aging,30 and a cohort using Swedish Health Care registers.31 Not all studies supported the association between surgical menopause and CHD. Contrary data emerged from analysis of the WHI observational study.19 In a 2011 analysis of the data, BSO was not associated with an increased risk of fatal or nonfatal CHD.19 The rate of HT use, however, was quite high, and 78.6% of women were identified as past or current users. The role of hysterectomy and oophorectomy on CHD may be time dependent, with proximity to natural menopause an important determinant. The degree of estrogen deficiency may also play a role in long-term risk, and may be partially, if not fully, mitigated by HT in the years that follow menopause. Cognitive functioning The “healthy cell bias” and the “critical time window” theories have emerged from investigations of Alzheimer disease, dementia risk, and cognitive functioning decline in relation to menopausal status at the time of oophorectomy.32 The
“healthy cell bias” theory suggests that estrogens are neuroprotective of healthy neurons, but accelerate degeneration of cells that have already undergone pathologic changes. The “critical time window” theory asserts that initiation of HT around the time of menopause can be beneficial, but if initiated in late menopause, can actually be deleterious. In one particular study, an increased risk of cognitive impairment or dementia was demonstrated in premenopausal women who underwent unilateral or bilateral oophorectomy, with a trend of increasing risk with younger age at the time of surgery. When ET was given until the age of 50 years, however, the association disappeared33 (Table 4). Similarly, the risk of death associated with neurological or mental disease was increased in women who underwent bilateral oophorectomy at age <45 years, although there was no association when women underwent bilateral oophorectomy at age >50 years.34 An increased risk of early-onset dementia (age <50 years), has been observed with younger age at hysterectomy and/or oophorectomy.35 Hysterectomy with BSO was associated with the greatest increased risk of dementia age <50 years. In a study specifically designed to assess whether HT can decrease the risk of dementia in women aged 65 years, there was no observed benefit to the initiation of HT in older postmenopausal women.36 In a study aimed at assessing the risk of Alzheimer disease and oophorectomy, earlier age of surgical menopause was associated with a steeper slope of cognitive decline, and a higher burden of Alzheimer disease neuropathology. Conversely, there were no such associations between age at natural menopause and either clinical or pathologic outcomes.37 Initiation of HT use within 5 years of menopause, and continued for at least 10 years, was associated with a decreased slope of decline in global function. When initiated 5 years after surgical menopause, there was no attenuation of the decline in cognitive functioning. In a separate study, oophorectomy after natural menopause was not identified as an important
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TABLE 2
Cancer risk, mortality, and oophorectomy Author Total cancer
Ovarian cancer
Breast cancer
Cohort
Major findings
Parker et al, 2013
Nurses’ Health Study
Higher mortality from total cancer associated with oophorectomy (HR, 1.16; 95% CI, 1.05e1.29)
Gaudet et al,23 2014
Cancer Prevention Study-II Nutrition
Lower risk of total cancer associated with hysterectomy and BSO (RR, 0.9; 95% CI, 0.85e0.96)
Altman et al,22 2016
Swedish Health Care registers Lower risk of total cancer associated with hysterectomy and BSO (HR, 0.92; 95% CI, 0.87e0.96) Same risk reduction observed with hysterectomy alone (HR, 0.93; 95% CI, 0.91e0.95)
Mytton et al,18 2017
English Healthcare Registries
Ovarian conservation associated with significantly lower rates of admission (HR, 0.83; 95% CI, 0.78e0.89) and death (HR, 0.54; 95% CI, 0.45e0.65) for any cancer
Jacoby et al,19 2011
Women’s Health Initiative Observational Study
Lower incidence of ovarian cancer with hysterectomy and BSO (0.02%) compared to hysterectomy alone (0.33%)
Parker et al,16 2013
Nurses’ Health Study
Decreased risk of ovarian cancer after hysterectomy with BSO (HR, 0.06; 95% CI, 0.02e0.17)
Chan et al,24 2014
Kaiser Permanente of Northern California
Decreased risk of ovarian cancer after hysterectomy with BSO (HR, 0.12; 95% CI, 0.05e0.28)
Parker et al,16 2013
Nurses’ Health Study
Lower risk of breast cancer with oophorectomy age <47.5 y
Robinson et al,28 2016
Carolina Breast Cancer Study
Premenopausal hysterectomy and BSO associated with reduced risk of breast cancer (OR, 0.60; 95% CI, 0.47e0.77)
Mytton et al,18 2017
English Healthcare Registries
Ovarian conservation associated with significantly increased rate of admission (HR, 1.34; 95% CI, 1.15e1.55), but significantly decreased rate of death from breast cancer (HR, 0.61; 95% CI, 0.39e0.94)
Women’s Health Initiative Observational Study
No significant difference in colorectal cancer risk observed with hysterectomy and BSO
Parker et al,16 2013
Nurses’ Health Study
Increased mortality from colorectal cancer in patients having undergone hysterectomy with BSO (HR, 1.49; 95% CI, 1.02e2.18)
Gaudet et al,23 2014
Cancer Prevention Study-II Nutrition
No statistically significant difference in colorectal cancer risk observed with hysterectomy and BSO
Luo et al,25 2016
Meta-analysis
Increased risk of colorectal cancer with hysterectomy and BSO (pooled RR, 1.22; 95% CI, 1.06e1.40)
16
Colorectal Jacoby et al,19 2011 cancer
Lung cancer
Segelman et al,26 2016 Swedish Patient Registry
30% Increased risk of colorectal cancer in women who underwent BSO (HR, 2.28; 95% CI, 1.33e3.91)
Mytton et al,18 2017
English Healthcare Registries
Ovarian conservation associated with significantly decreased rate of death from colon cancer (HR, 0.47; 95% CI, 0.25e0.88)
Koushik et al,27 2009
Population-based case-control Increased risk of lung cancer in women having undergone surgical menopause with BSO (OR 1.90; 95% CI, 1.18e3.06)
Jacoby et al,19 2011
Women’s Health Initiative Observational Study
No significant difference in lung cancer risk observed with hysterectomy and BSO
Parker et al,16 2013
Nurses’ Health Study
Increased risk of lung cancer mortality (HR, 1.29; 95% CI, 1.04e1.61) with oophorectomy
Gaudet et al,23 2014
Cancer Prevention Study-II Nutrition
No statistically significant difference in lung cancer risk observed with hysterectomy and BSO
Mytton et al,18 2017
English Healthcare Registries
Ovarian conservation associated with significantly decreased rate of admission (HR, 0.66; 95% CI, 0.48e0.91), and no difference in rate of death from lung cancer
BSO, bilateral salpingo-oophorectomy; CI, confidence interval; HR, hazard ratio; OR, odds ratio; RR, relative risk. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
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TABLE 3
Coronary heart disease risk, mortality, and oophorectomy Cohort
Deleterious effect of BSO
Colditz et al, 1987
Nurses’ Health Study
Yes
Increased risk of CHD after BSO in women who were never treated with HT (rate ratio, 2.2; 95% CI, 1.2e4.2) Use of HT in early postmenopausal period after BSO eliminated increased risk
Parker et al,15 2009
Nurses’ Health Study
Yes
Increased risk of CHD at all ages after BSO (HR, 1.17; 95% CI, 1.02e1.35) Greater increased risk observed after BSO age <45 y (HR, 1.26; 95% CI, 1.04e1.54) Greatest increased risk observed after BSO age <50 y, and not treated with HT (HR, 1.98; 95% CI, 1.18e3.32)
Rivera et al,30 2009
Mayo Clinic Cohort Study of Oophorectomy and Aging
Yes
Most dramatic increase in CHD mortality observed with BSO <45 y, either not treated with HT to age 45 y, or interrupted treatment age <45 y (HR, 1.84; 95% CI 1.27e2.68) No increase in CHD mortality when women were treated with HT until age 45 y
Ingelsson et al,31 2011
Swedish Health Care registers
Yes
Hysterectomy with BSO associated with 40% increased risk of CHD in women age <50 y (HR, 2.22; 95% CI, 1.01e4.83)
Jacoby et al,19 2011
Women’s Health Initiative
No
BSO not associated with increased risk of CHD in all-comers, or women who never used HT
Author 29
Major findings
BSO, bilateral salpingo-oophorectomy; CHD, coronary heart disease; CI, confidence interval; HR, hazard ratio; HT, hormone therapy. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
determinant of Alzheimer disease risk in older women.32 Taken together, the data on oophorectomy and surgical menopause support a deleterious effect of estrogen deficiency on cognitive functioning, which is both age and dose dependent. Global cognitive decline, dementia, and Alzheimer disease risk may share a common correlate with estrogen deficiency. HT may mitigate some of the neurologic effects of estrogen deficiency when continued until the natural age of menopause or initiated in the perimenopausal period. Postmenopausal oophorectomy and natural menopause do not appear to confer the same risk on cognitive functioning as surgical menopause.
Sexual functioning Hysterectomy, particularly when women are highly symptomatic, can be beneficial to sexual functioning. In the Maryland Women’s Health Study, there was widespread improvement in the percentage of women who engaged in sexual relations after hysterectomy.38 An
important finding, however, was that BSO was associated with anorgasmia 1 year postoperatively, and that each year of age increased the odds of not experiencing orgasms 1 year after hysterectomy by 7%. Some studies demonstrated a deleterious effect of BSO on sexual functioning,39-42 while others have not38,43,44 (Table 5). The results of many of these studies are difficult to interpret, given the varied use of HT.38,39 Reduced androgen levels may be associated with low libido and development of hypoactive sexual desire disorder (HSDD). The effects on sexual functioning are not just dependent on the absolute changes in hormone levels, rather there appears to be a complex relationship among abruptness of hormone loss, proximity to menopause, and use of HT. One population in which there is less controversy over the decision to proceed with BSO at a young age is women with known BRCA gene mutations or otherwise increased risk of ovarian cancer. In these women, hormone loss is abrupt, and HT initiation is varied. Two studies examined the
impact of BSO and HT on women undergoing risk-reducing oophorectomy. A large observational study of high-risk premenopausal women in The Netherlands45 compared women undergoing gynecologic screening with women undergoing prophylactic oophorectomy. Of those undergoing oophorectomy, 47% reported HT use. All 3 groups (screening, oophorectomy with HT, oophorectomy without HT) reported comparable levels of sexual functioning, but both users of HT and nonusers in the oophorectomy group reported significantly more sexual discomfort. Thus, in this population, HT did not appear to alleviate sexual discomfort. In a prospective evaluation of BRCA mutation carriers undergoing oophorectomy, the majority of women who were premenopausal at the time of surgery experienced a significant decline in sexual functioning, particularly decreases in the domains of desire and vaginal dryness.46 Women who were taking HT reported better sexual functioning than nonusers, but worse than presurgical levels. At 1 year
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TABLE 4
Cognitive functioning, mortality, and oophorectomy Author Imtiaz et al, 2014
Deleterious effect of BSO
Cohort 32
Bove et al,37 2014
Major findings
No All women with clinically verified AD, residing in Finland in 2005 91.8% of Women were age >51 y at time of BSO, therefore predominantly postmenopausal
Utilized information from national registries to determine if oophorectomy with or without hysterectomy is associated with AD risk No significant difference in relative risk of AD among women who underwent BSO and/or hysterectomy Concluded that surgery after natural menopause is not important determinant of AD risk
Participants from 2 longitudinal studies of cognitive decline 1/3 Previously undergone surgical menopause
Earlier age at surgical menopause was associated with steeper slope of global cognitive decline Earlier age at surgical menopause was associated with higher burden of AD neuropathology HRT use within 5 y of surgical menopause, for at least 10 y, was associated with decreased slope of decline in global cognition
Yes
Phung et al,35 Register-based historical cohort of 2010 Danish women Included women who underwent hysterectomy oophorectomy
Yes, but unclear effect Increased risk of dementia with hysterectomy of hysterectomy alone alone (RR, 1.38; 95% CI, 1.07e1.78), hysterectomy þ USO (RR, 2.10; 95% CI, 1.28e3.45), and hysterectomy þ BSO (RR, 2.33; 95% CI, 1.44e3.77)
Rivera et al,34 Participants of Mayo Clinic Cohort 2009 Study of Oophorectomy and Aging Women who underwent premenopausal oophorectomy
Yes
Increased risk of death associated with neurological or mental disease in women who underwent bilateral oophorectomy <45 y (HR, 5.24; 95% CI, 2.02e13.6) No association identified in women who underwent oophorectomy >45 y
Rocca et al,33 Participants of Mayo Clinic Cohort 2007 Study of Oophorectomy and Aging Women who underwent hysterectomy oophorectomy
Yes
Oophorectomy associated with increased risk of cognitive impairment or dementia, with trend of increasing risk with younger age at time of surgery Significantly increased risk when oophorectomy was performed age <49 y (HR, 1.70; 95% CI, 1.15e2.51), and HT not given through age 50 y
AD, Alzheimer disease; BSO, bilateral salpingo-oophorectomy; CI, confidence interval; HR, hazard ratio; HRT, hormone replacement therapy; HT, hormone therapy; RR, relative risk; USO, unilateral salpingo-ophorectomy.. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
postoperatively, there was a decline in sexual functioning regardless of HT use. HT did appear to alleviate the discomfort of surgical menopause, but the decline in sexual pleasure was unchanged. HSDD, presumably from an abrupt loss of androgens, has been linked to surgical menopause. The Women’s International Study of Health and Sexuality47,48 cross-sectional survey studied the prevalence of HSDD in surgically menopausal women. The data from the US48 and European47 cohorts yielded similar results as the percentage of women with HSDD was significantly higher in the young surgically menopausal population when compared to age-matched premenopausal women.
HT mitigates physical signs of genitourinary atrophy, but not necessarily key components of sexual functioning such as desire, orgasm, and satisfaction. BSO at any age confers a risk of HSDD, but is demonstrated most robustly in the population of women age <50 years at the time of surgery.
Osteoporotic fracture risk Osteoporosis and bone fracture risk play an important role in postmenopausal women’s health. Hip fracture in particular can result in increased mortality, as well as loss of mobility and need for long-term care.49,50 There is clear and convincing evidence that estrogen deficiency is associated with loss of bone mass, particularly when it occurs early in
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life. Current evidence suggests that 75% of bone loss occurs during the first 2 decades after menopause, and is attributable to estrogen deficiency, rather than aging.51 Bone mineral density (BMD) from loss of exogenous estrogen occurs much more rapidly than in menopause. A longitudinal observational study of >80,000 women evaluated the effects of HT cessation on bone loss.52 Longer duration of HT cessation was linearly correlated with lower BMD, and hip fracture risk significantly increased with longer duration of HT cessation. The protective association of HT with hip fracture disappeared within 2 years of cessation, demonstrating the absence of a durable long-term benefit.
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TABLE 5
Sexual functioning, hysterectomy, and oophorectomy Author
Cohort
Deleterious effect of BSO
Major findings
Chen et al, 2013
Yes Women aged 45e60 y Having undergone hysterectomy BSO Not given HRT
Utilized FSFI; score of <26 indicated sexual dysfunction More patients in hysterectomy-alone group scored >30, and women in that group recorded better scores in sexual performance, arousal, orgasm, satisfaction, pain, and vaginal lubrication No difference in sexual interest between groups
Rodriguez et al,40 2012
Sexually active women 1 y after Hysterectomy BSO for benign indications
No, but unclear effect of hysterectomy alone
Used FSFI; score of <26.55 indicated sexual dysfunction Mean score was 19.4, with all participants scoring <26.55 No difference in sexual functioning by oophorectomy status No difference in sexual functioning by HT status
Sozeri-Varma et al,41 2011
Women undergoing hysterectomy BSO
No
Evaluated measures of anxiety (Hamilton Anxiety Rating Scale), depression (Hamilton Depression Rating Scale), and sexual satisfaction (Golombok Rust Inventory of Sexual Satisfaction) at baseline, 3 mo, and 6 mo postoperatively No observed differences between patients by BSO status No observed differences between HRT status
Finch et al,46 2011
Women aged 30e70 y Undergoing risk-reducing BSO for known BRCA mutation
Yes
Utilized Menopausal-Specific Quality-of-Life questionnaire Majority of women who were premenopausal at time of surgery experienced decline in sexual functioning (decrease in sexual desire, vaginal dryness, and avoidance of intimacy) Women who were premenopausal at time of surgery, and used HT postoperatively, had better sexual functioning than those who did not use HT, but still worse than presurgical levels Women who were postmenopausal at time of surgery experienced small but statistically significant decrease in sexual functioning
Celik et al,43 2008
Postmenopausal women Undergoing TAH/BSO or TVH/BSO
Yes, but unclear Utilized FSFI Hysterectomy with BSO by either route resulted effect of in significantly reduces FSFI score at 6 mo hysterectomy postoperatively alone
Teplin et al,42 2007
Premenopausal women Participants of medicine or surgery trial, and total or supracervical hysterectomy trial
No
Utilized Medical Outcomes Study (MOS) Sexual Problems Scale No statistically significant difference in measures of sexual functioning by BSO status HT unexpectedly associated with worse outcomes
Yes
Utilized Profile of Female Sexual Function and Personal Distress Scale to determine prevalence of HSDD among US women Percentage of women aged 20e49 y who were surgically menopausal and distressed by their low desire (26%) was significantly greater than premenopausal women of similar age (14%) These results are despite fact that majority of women aged 20e49 y who were postmenopausal reported using estrogen therapy
44
Leiblum et al,48 2006 Surgically menopausal women aged 20e49 y Surgically menopausal women aged 50e70 y Premenopausal women aged 20e49 y Naturally menopausal women aged 50e70 y
Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
(continued)
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TABLE 5
Sexual functioning, hysterectomy, and oophorectomy (continued) Author
Deleterious effect of BSO
Cohort
Major findings
Same participant cohorts as Leiblum et al,48 2006
Yes
Utilized Profile of Female Sexual Function and Personal Distress Scale to determine prevalence of HSDD among European women Women of any age group who underwent bilateral oophorectomy were more likely to meet criteria for HSDD than their reproductive-aged counterparts Likelihood of experiencing low desire and HSDD was significantly less among HT users
Madalinska et al,45 2006
Premenopausal women at high risk of ovarian cancer Having undergone prophylactic BSO, with or without HT, or undergoing screening
Yes
Utilized Sexual Activity Questionnaire to measure sexual functioning Surgically menopausal women using HT, nonusers of HT, and women in screening group reported comparable levels of sexual functioning, but BSO groups reported significantly more sexual discomfort
Aziz et al,39 2005
Perimenopausal women aged 45e55 y Unclear Having undergone hysterectomy BSO
Utilized McCoy Female Sexuality Questionnaire to evaluate presurgical and postsurgical sexual functioning All oophorectomized women, and women with climacteric symptoms were encouraged to initiate HRT; therefore 98% of oophorectomized women and 23% of nonoophorectomized women initiated HT Hysterectomy-only group scored significantly higher on McCoy Female Sexuality Questionnaire, both preoperatively and postoperatively, when compared to participants undergoing hysterectomy with BSO Similar changes in scores were noted between groups, which was overall worse 1 y postoperatively
Rhodes et al,38 1999
Participants of Maryland Women’s Health Study Premenopausal and postmenopausal women undergoing hysterectomy BSO for benign conditions
Designed to measure outcomes and effectiveness of hysterectomy for benign conditions Frequency of sexual relations increased after hysterectomy Percentage of women experiencing dyspareunia dropped after hysterectomy Orgasm frequency increased after hysterectomy Women who underwent BSO were significantly more likely to be anorgasmic at 12 mo postoperatively
Dennerstein et al, 2006
47
Yes
BSO, bilateral salpingo-oophorectomy; FSFI, Female Sexual Function Index; HRT, hormone replacement therapy; HSDD, hypoactive sexual desire disorder; HT, hormone therapy; TAH, total abdominal hysterectomy; TVH, total vaginal hysterectomy. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
What is less clear is the effect of oophorectomy on bone loss and fracture risk in older postmenopausal women. A statistically significant increase in fracture rate was observed in one study of women who underwent BSO after natural menopause.53 In fact, there was both an increase in the rate of traditional osteoporotic fractures, as well as fracture at any of the remaining skeletal sites. The loss of BMD that follows menopause is irrespective of whether it is
surgical or natural. HT may mitigate these losses, but the effect appears to be limited to the duration of use, with loss of benefit several years after cessation. There does, however, appear to be some protective effect of the postmenopausal ovary, perhaps due to the small production of androgens.
Subsequent surgery Decreased risk of subsequent surgery for ovarian pathology has been cited as one
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of the benefits of BSO at the time of hysterectomy. Recently, a study presented long-term follow-up with an agematched referent group to evaluate the cumulative incidence of subsequent oophorectomy in women who previously underwent hysterectomy with ovarian preservation.54 Nearly 5000 cases were compared to a similar number of referent women, with a median followup of approximately 20 years. The cumulative incidence of subsequent
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ajog.org oophorectomy was 3.5%, 6.2%, and 9.2% among case group participants at 10, 20, and 30 years, compared to 1.9%, 4.8%, and 7.3% among referent group participants. While the overall risk of subsequent oophorectomy among case group participants was significantly higher than among referent group participants (HR, 1.20; 95% CI, 1.02e1.42), the incidence of oophorectomy after hysterectomy at 30-year follow-up was only 1.9 percentage points higher than the incidence of oophorectomy in referent women with intact reproductive organs. We interpret this difference to be clinically insignificant, and as such, does not support the routine removal of ovaries for the purpose of avoiding future surgery.
Ovarian cancer prevention The Society of Gynecologic Oncology (SGO) released revised recommendations in 2015 for the prevention of ovarian cancer,55 which focused on the role of the fallopian tube as a conduit for retrograde menstruation, and a possible source of neoplastic epithelial cells. A recent paradigm shift in our understanding of the pathogenesis of ovarian cancer has led to the classification of type 1 tumors, which tend to present at earlier stages and are thought to arise from precursor lesions, and type 2 tumors, which tend to present at advanced stages and are thought to arise from neoplastic progression of fallopian tube epithelial cells. Type 1 tumors include low-grade serous, low-grade endometrioid, clear cell, and mucinous histology types. They are hypothesized to result from endometriosis, inflammation, uninterrupted and frequent ovulation, and the overall microenvironment, including reactive oxidative species. The morphologic, genetic, and molecular similarities of endometrioid and clear cell carcinomas with endometriotic cysts, has provided support for the hypothesis of retrograde menstruation and the derivation from the endometrium in those subtypes. Occlusion of the tubes should therefore decrease the risk of some type 1 tumors, and in fact, tubal ligation is associated with a 34% overall risk reduction in
ovarian cancer in women of average risk.56 Type 2 tumors include high-grade serous carcinomas, high-grade endometrioid adenocarcinomas, undifferentiated carcinomas, and carcinosarcomas. These cancers contain p53 mutations in an overwhelming majority of cases. In both BRCA1 and BRCA2 mutation carriers, as well as in sporadic cases of serous ovarian cancers, the p53 mutation identified in the ovarian tumor frequently matches mutations seen in precursor lesions of the fallopian tube. Salpingectomy would therefore be expected to reduce the incidence of type 2 ovarian cancers, as well as some type 1 ovarian cancers. The SGO has proposed several strategies aimed at the prevention of ovarian cancer, and include oral contraceptive use, tubal sterilization (which can include salpingectomy), and opportunistic salpingectomy at the time of pelvic surgery. Risk-reducing salpingooophorectomy is therefore reserved for women with high hereditary risk of breast and ovarian cancer.55 In Committee Opinion number 620, the American Congress of Obstetricians and Gynecologists proposes salpingectomy at the time of hysterectomy, or as a means of tubal sterilization, but cautions against a change in the approach of hysterectomy or sterilization, based solely on the benefits of salpingectomy.57
Conclusions There is a deleterious effect of oophorectomy on overall mortality, particularly when completed at age <50 years. While HTmay mitigate the increased mortality with oophorectomy, at no age does there appear to be a survival benefit. Based on Markov modeling, ovarian conservation may even confer a long-term survival benefit until the age of 65 years. There is a significantly lower rate of ovarian cancer observed after oophorectomy at all ages, and a decreased risk of breast cancer when oophorectomy is completed at age <47.5 years. The relationship between oophorectomy and all-site
cancer, colorectal cancer, and lung cancer is unclear, although most data favor a lower risk with ovarian conservation. The existing data do not universally implicate BSO in CHD, but there are no data that support a beneficial effect of oophorectomy on CHD. In aggregate, ovarian preservation is associated with an observed benefit to cardiovascular health. Global cognitive decline, dementia, and Alzheimer disease risk may share a common correlate with estrogen deficiency. Surgical menopause appears to confer a risk that is not observed with postmenopausal oophorectomy and natural menopause. BSO at the time of hysterectomy confers a deleterious effect on sexual functioning. HT mitigates physical signs of genitourinary atrophy, but not necessarily key components of sexual functioning, such as desire, orgasm, or satisfaction. BSO at any age confers a risk of HSDD. Estrogen deficiency following natural or surgical menopause is associated with BMD loss and increased fracture risk. HT can halt bone density loss, but the effect is limited to the duration of use, and significant losses can be observed within 2 years of cessation. Although the risk of subsequent surgery following BSO is decreased, this decrease is minimal and of questionable clinical significance. Current data do not support the routine removal of ovaries for the purpose of avoiding future surgery. In the absence of a genetic susceptibility mutation, tubal ligation, salpingectomy, and hysterectomy itself can provide ovarian cancer risk reduction to women of average risk, without the untoward effects of oophorectomy, and without the need for HT. -
REFERENCES 1. Jacoby VL, Vittinghoff E, Nakagawa S, et al. Factors associated with undergoing bilateral salpingo-oophorectomy at the time of hysterectomy for benign conditions. Obstet Gynecol 2009;113:1259-67.
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ajog.org 16. Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol 2013;121:709-16. 17. Gierach GL, Pfeiffer RM, Patel DA, et al. Long-term overall and disease-specific mortality associated with benign gynecologic surgery performed at different ages. Menopause 2014;21. 592-101. 18. Mytton J, Evison F, Chilton PJ, Lilford RJ. Removal of all ovarian tissue versus conserving ovarian tissue at time of hysterectomy in premenopausal patients with benign disease: study using routine data and data linkage. BMJ 2017;356:j372. 19. Jacoby VL, Grady D, Wactawski-Wende J, et al. Oophorectomy vs ovarian conservation with hysterectomy: cardiovascular disease, hip fracture, and cancer in the Women’s Health Initiative observational study. Arch Intern Med 2011;171:760-8. 20. Averette HE, Nguyen HN. The role of prophylactic oophorectomy in cancer prevention. Gynecol Oncol 1994;55:S38-41. 21. Speroff T, Dawson NV, Speroff L, Haber RJ. A risk-benefit analysis of elective bilateral oophorectomy: effect of changes in compliance with estrogen therapy on outcome. Am J Obstet Gynecol 1991;164:165-74. 22. Altman D, Yin L, Falconer H. Long-term cancer risk after hysterectomy on benign indications: population-based cohort study. Int J Cancer 2016;138:2631-8. 23. Gaudet MM, Gapstur SM, Sun J, Teras LR, Campbell PT, Patel AV. Oophorectomy and hysterectomy and cancer incidence in the Cancer Prevention Study-II Nutrition Cohort. Obstet Gynecol 2014;123:1247-55. 24. Chan JK, Urban R, Capra AM, et al. Ovarian cancer rates after hysterectomy with and without salpingo-oophorectomy. Obstet Gynecol 2014;123:65-72. 25. Luo G, Zhang Y, Wang L, et al. Risk of colorectal cancer with hysterectomy and oophorectomy: a systematic review and metaanalysis. Int J Surg 2016;34:88-95. 26. Segelman J, Lindstrom L, Frisell J, Lu Y. Population-based analysis of colorectal cancer risk after oophorectomy. Br J Surg 2016;103: 908-15. 27. Koushik A, Parent ME, Siemiatycki J. Characteristics of menstruation and pregnancy and the risk of lung cancer in women. Int J Cancer 2009;125:2428-33. 28. Robinson WR, Nichols HB, Tse CK, Olshan AF, Troester MA. Associations of premenopausal hysterectomy and oophorectomy with breast cancer among black and white women: the Carolina Breast Cancer Study, 1993-2001. Am J Epidemiol 2016;184:388-99. 29. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987;316:1105-10. 30. Rivera CM, Grossardt BR, Rhodes DJ, et al. Increased cardiovascular mortality after early
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bilateral oophorectomy. Menopause 2009;16: 15-23. 31. Ingelsson E, Lundholm C, Johansson ALV, Altman D. Hysterectomy and risk of cardiovascular disease: a population-based cohort study. Eur Heart J 2011;32:745-50. 32. Imtiaz B, Tuppurainen M, Tiihonen M, et al. Oophorectomy, hysterectomy, and risk of Alzheimer’s disease: a nationwide case-control study. J Alzheimers Dis 2014;42:575-81. 33. Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007;69: 1074-83. 34. Rivera CM, Grossardt BR, Rhodes DJ, Rocca WA. Increased mortality for neurological and mental diseases following early bilateral oophorectomy. Neuroepidemiology 2009;33: 32-40. 35. Phung TKT, Waltoft BL, Laursen TM, et al. Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study. Dement Geriatr Cogn Disord 2010;30:43-50. 36. Craig MC, Maki PM, Murphy DG. The Women’s Health Initiative memory study: findings and implications for treatment. Lancet Neurol 2005;4:190-4. 37. Bove R, Secor E, Chibnik LB, et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 2014;82:222-9. 38. Rhodes JC, Kjerulff KH, Langenberg PW, Guzinski GM. Hysterectomy and sexual functioning. JAMA 1999;282:1934-41. 39. Aziz A, Bergquist C, Nordholm L, Moller A, Silfverstolpe G. Prophylactic oophorectomy at elective hysterectomy. Effects on psychological well-being at 1-year follow-up and its correlations to sexuality. Maturitas 2005;51: 349-57. 40. Rodriguez MC, Chedraui P, Schwager G, Hidalgo L, Perez-Lopez FR. Assessment of sexuality after hysterectomy using the Female Sexual Function Index. J Obstet Gynaecol 2012;32:180-4. 41. Sozeri-Varma G, Kalkan-Oguzhanoglu N, Karadag F, Ozdel O. The effect of hysterectomy and/or oophorectomy on sexual satisfaction. Climacteric 2011;14:275-81. 42. Teplin V, Vittinghoff E, Lin F, Learman LA, Richter HE, Kuppermann M. Oophorectomy in premenopausal women: health-related quality of life and sexual functioning. Obstet Gynecol 2007;109:347-54. 43. Celik H, Gurates B, Yavuz A, Nurkalem C, Hanay F, Kavak B. The effect of hysterectomy and bilaterally salpingo-oophorectomy on sexual function in post-menopausal women. Maturitas 2008;61:358-63. 44. Chen X, Guo T, Li B. Influence of prophylactic oophorectomy on mood and sexual function in women of menopausal transition or postmenopausal period. Arch Gynecol Obstet 2013;288:1101-6. 45. Madalinska JB, van Beurden M, Bleiker EM, et al. The impact of hormone replacement
Expert Reviews
ajog.org therapy on menopausal symptoms in younger high-risk women after prophylactic salpingooophorectomy. J Clin Oncol 2006;24:3576-82. 46. Finch A, Metcalfe KA, Chiang JK, et al. The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation. Gynecol Oncol 2011;121:163-8. 47. Dennerstein L, Koochaki P, Barton I, Graziottin A. Hypoactive sexual desire disorder in menopausal women: a survey of Western European women. J Sex Med 2006;3:212-22. 48. Leiblum SR, Koochaki PE, Rodenberg CA, Barton IP, Rosen RC. Hypoactive sexual desire disorder in postmenopausal women: US results from the Women’s International Study of Health and Sexuality (WISHeS). Menopause 2006;13: 46-56.
49. Gambacciani M, Ciaponi M, Genazzani AR. The HRT misuse and osteoporosis epidemic: a possible future scenario. Climacteric 2007;10: 273-5. 50. Owen RA, Melton LJ III, Gallagher JC, Riggs BL. The national cost of acute care of hip fractures associated with osteoporosis. Clin Orthop Relat Res 1980;(150):172-6. 51. Richelson LS, Wahner HW, Melton LJ III, Riggs BL. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 1984;311: 1273-5. 52. Karim R, Dell RM, Greene DF, Mack WJ, Gallagher JC, Hodis HN. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization. Menopause 2011;18:1172-7.
53. Melton LJ III, Khosla S, Malkasian GD, Achenbach SJ, Oberg AL, Riggs BL. Fracture risk after bilateral oophorectomy in elderly women. J Bone Miner Res 2003;18:900-5. 54. Casiano ER, Trabuco EC, Bharucha AE, et al. Risk of oophorectomy after hysterectomy. Obstet Gynecol 2013;121:1069-74. 55. Walker JL, Powell CB, Chen LM, et al. Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer 2015;121:2108-20. 56. Cibula D, Widschwendter M, Majek O, Dusek L. Tubal ligation and the risk of ovarian cancer: review and meta-analysis. Hum Reprod Update 2011;17:55-67. 57. Committee on Gynecologic Practice. Salpingectomy for ovarian cancer prevention. Committee opinion no. 620. Obstet Gynecol 2015;125:279-81.
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Ovarian conservation vs removal at the time of benign hysterectomy Marisa R. Adelman, MD; Howard T. Sharp, MD
Introduction Oophorectomy at the time of hysterectomy occurs at a rate of 40-50% in the United States.1-5 Commonly cited rationales for bilateral salpingooophorectomy (BSO) are prevention of ovarian cancer and decreased risk of subsequent surgery. The sequelae of BSO include increased mortality due to all causes, cardiovascular disease, deficits of cognitive and sexual functioning, and osteoporosis. Historically, hormone therapy (HT) has been used to mitigate the effects of estrogen deficiency. In a study of HT compliance, 3% of women discontinued HT by 2 years, 20% by 5 years, and 67% by 10 years.6 The Women’s Health Initiative (WHI) observed a discontinuation rate of 42% at an average of 5.2 years of follow-up.7 Although the primary objective of the WHI was to evaluate whether HT had favorable effects on coronary heart disease (CHD),7,8 its main effect was to change the prescribing practice of HT. Importantly, the postmenopausal ovary appears to be an ongoing site of testosterone production. A decline in serum androgens is observed throughout the reproductive years, with minimal change in the midlife, and a slight increase in the seventh decade. While natural menopause does not seem to affect serum androgen levels, oophorectomy results in significantly lower levels of total and free testosterone.9 The
From the Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT. Received May 11, 2017; revised July 14, 2017; accepted July 31, 2017. The authors report no conflict of interest. Corresponding author: Marisa R. Adelman, MD. [email protected] 0002-9378/$36.00 ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2017.07.037
Over the last 2 decades, the rate of oophorectomy at the time of hysterectomy in the United States has consistently been between 40-50%. A decline in hormone use has been observed since the release of the principal results of the Women’s Health Initiative. Oophorectomy appears to be associated with an increased risk of coronary heart disease, as well as deleterious effects on overall mortality, cognitive functioning, and sexual functioning. Estrogen deficiency from surgical menopause is associated with bone mineral density loss and increased fracture risk. While hormone therapy may mitigate these effects, at no age does there appear to be a survival benefit associated with oophorectomy. Reduction of ovarian cancer risk may be accomplished with salpingectomy at the time of hysterectomy. Key words: morbidity, mortality, oophorectomy, ovarian cancer, ovarian conservation
postmenopausal ovary is therefore a source of androgens in older women, and provides precursors for estrogen metabolism. This is particularly relevant to bone health, cardiovascular health, sexual functioning, and cognitive functioning. In this article, we consider recent trends in oophorectomy, the risks and benefits, the role of HT, and alternatives for risk reduction of ovarian cancer.
Trends in oophorectomy Multiple large population-based databases have examined the overall rate of oophorectomy at the time of hysterectomy in the United States. The percentage has been consistently in the mid-40s (43.7%-46.7%).1-5 After the release of the initial WHI results in 2002, an acute decline in BSO rate was noted.3,4,10 The decline was observed in all age groups, but most notably in women aged 45-49 years.10 While the age-adjusted risk of oophorectomy with hysterectomy declined in women 50 years of age, the risk for women age >50 years increased.11 Age has repeatedly been identified as an independent risk factor for elective oophorectomy during hysterectomy, starting as young as 45 years. Lowder et al11 observed an odds ratio of 11.4 (95% confidence interval [CI],
10.2e12.7) for oophorectomy at age 45-49 years, and 17.7 (95% CI, 15.6e20.2) at age 50-54 years, when compared to women <35 years old. Similarly, Asante et al10 observed the highest rates of elective oophorectomy in women aged 45-49 years, followed by women aged 50-54 years. In a study by Jacoby et al,1 the odds of undergoing BSO increased approximately 30% with each year of advancing age between 40-49 years. Despite the recent increase in ovarian conservation for women aged 45-49 years, the rate of oophorectomy in this age group is approximately 60%.1,5 The rate of oophorectomy in women age of >55 years is 65-75%.1,3,5 While age appears to play the most prominent role in the decision to remove or retain ovaries, several clinical and demographic variables have also been identified. A personal history of breast cancer or a family history of breast or ovarian cancer is associated with elective oophorectomy during hysterectomy, even when genetic susceptibility mutations are not identified.2,4
All-cause mortality In 2005, Parker et al12 published a Markov decision analysis to estimate the optimal strategy for maximizing survival in women at average risk of ovarian cancer. The risks and benefits of
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TABLE 1
All-cause mortality and oophorectomy Author
Deleterious effect of BSO
Cohort
Major findings
Ossewaard et al, 2005
Dutch breast cancer screening cohort
Yes
2% Decrease in total mortality per year of delayed menopause
Rocca et al,14 2006
Mayo Clinic Cohort Study of Oophorectomy and Aging
Yes
Increased risk of mortality with bilateral oophorectomy age <45 y (HR, 1.67; 95% CI, 1.16e2.40)
Parker et al,15 2009 Parker et al,16 2013
Nurses’ Health Study
Yes
Oophorectomy associated with increased risk of all-cause death (HR, 1.13; 95% CI, 1.06e1.21) Even higher risk of all-cause death observed in women who underwent oophorectomy age <50 y, and never used estrogen therapy (HR, 1.41; 95% CI, 1.04e1.92)
Jacoby et al,19 2011
Women’s Health Initiative
No
BSO not associated with increased risk of death in multivariate analysis (HR, 0.98; 95% CI, 0.87e1.10) BSO not associated with increased risk of death in subset of women who never used HT (HR, 0.99; 95% CI, 0.80e1.23)
Gierach et al,17 2014
Breast Cancer Detection Demonstration Project
Yes
Women who underwent BSO by age 35 y had increased risk of death from any cause (HR, 1.20; 95% CI, 1.08e1.34), which progressively decreased when surgery was performed later in life By age 50 y, risk was no longer increased (HR, 1.05; 95% CI, 0.99e1.10)
Mytton et al,18 2017
English Healthcare Registries
Yes
Ovarian conservation was associated with significantly lower rate of all-cause death (HR, 0.64; 95% CI, 0.55e0.73)
13
BSO, bilateral salpingo-oophorectomy; CI, confidence interval; HR, hazard ratio; HT, hormone therapy. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
oophorectomy at the time of surgery for benign gynecologic disease were considered, and included overall mortality, as well as mortality from CHD, hip fracture, stroke, ovarian cancer, and breast cancer. The highest rates of survival were observed in the ovarian conservation cohorts, either with or without estrogen therapy (ET), and were measured in survival to age 80 years. Oophorectomy with ET was associated with a comparable survival (62.15%) to ovarian conservation with ET (62.75%), while oophorectomy without ET was associated with a much lower proportion of survival (53.88%). Similar results have been observed in a variety of large cohort studies (Table 1), including a Dutch breast cancer screening cohort,13 the Mayo Clinic Cohort Study of Oophorectomy and Aging,14 the Nurses’ Health Study,15,16 the Breast Cancer Detection
Demonstration Project,17 as well as a retrospective analysis of English national databases.18 An increased risk of death from any cause was particularly apparent in women who underwent oophorectomy age <45-50 years, and never used ET. At no age was there an overall survival benefit associated with bilateral oophorectomy at the time of hysterectomy. The only large prospective observational cohort to not demonstrate a deleterious effect of BSO on mortality was the WHI.19 In multivariate analysis, BSO was not associated with an increased risk of overall mortality. However, the differences in study demographics should be taken into consideration when this cohort is used for comparison. The average age at the time of enrollment was 63 years, average follow-up was 7.6 years, and 78.6% of the cohort were past or current users of
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HT. The relatively older age at the time of enrollment, shorter follow-up, and prevalence of HT use may account for the absence of any interaction between BSO and mortality that was observed in the other studies. In summary, the vast majority of the literature supports a deleterious effect of oophorectomy on overall mortality, particularly when performed at age <50 years. ET appears to mitigate the increase in overall mortality associated with oophorectomy, but at no age was a survival benefit shown. Based on Markov modeling, ovarian conservation may even confer a long-term survival benefit until the age of 65 years.12
Cancer risk and mortality It has been estimated that 1000 cases of ovarian cancer could be prevented annually, if every woman age >40 years underwent BSO at the time of
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ajog.org hysterectomy.20 This estimate has frequently been taken out of context, as the long-term benefit is predicated on the assumption that oophorectomized women will be completely compliant with estrogen replacement therapy. A Markov analysis by Speroff et al21 identified a shorter life expectancy in women who undergo oophorectomy age <45 years, with typical HT rates. The data on hysterectomy, oophorectomy, and all-cause cancer risk as well as mortality show mixed conclusions with mostly marginal magnitudes of effect16,22,23 (Table 2). Hysterectomy with oophorectomy, as would be expected, has a dramatic impact on ovarian cancer risk reduction16,19,24 but there also appears to be benefit to hysterectomy alone. The data are mixed on colorectal cancer risk relative to oophorectomy,16,18,19,23,25,26 as well as lung cancer risk.16,18,19,23,27 Oophorectomy prior to menopause has been associated with a lower risk of death from breast cancer15,16,28 in several studies, and may even affect some women’s attitude towards oophorectomy at the time of hysterectomy. Interestingly, retrospective analysis by Mytton et al18 of all English women aged 35-45 years undergoing hysterectomy for benign indications found that there was an increased incidence of breast cancer with ovarian conservation, but the rate of death from breast cancer was actually significantly lower (hazard ratio [HR], 0.61; 95% CI, 0.39e0.94). The authors comment that with longer follow-up, it is possible that the rate of death from breast cancer may eventually rise. This study included 113,678 patients over a 10-year study period, and represents the largest study to examine the relationship between oophorectomy and adverse outcomes. In this study, the rate of death from any cancer was significantly lower in the ovarian conservation group (HR, 0.54; 95% CI, 0.45e0.65). The fact that BSO is associated with a lower incidence of breast and ovarian cancer may be offset by the higher rate of death from all cancer, and should be included in the discussion of women considering BSO for the purpose of cancer risk reduction.
CHD risk and mortality The Nurses’ Health Study cohort demonstrated that women who had undergone bilateral oophorectomy, and had never taken estrogen after menopause, had an increased risk of CHD29 (Table 3). The use of ET in the early postmenopausal period of surgically menopausal women, however, appeared to eliminate the increased risk, while the use of ET after natural menopause had no effect on risk. After 24 years of followup data from the Nurses’ Health Study, oophorectomy is still associated with an increased risk of CHD at all ages of oophorectomy (HR, 1.17; 95% CI, 1.02e1.35), but particularly for women <45 years old (HR, 1.26; 95% CI, 1.04e1.54).15 The risk was further illustrated in women who underwent oophorectomy at age <50 years, but who never used ET (HR, 1.98; 95% CI, 1.18e3.32). There have been several other large studies that associated CHD with hysterectomy and oophorectomy, including the Mayo Clinic Cohort Study of Oophorectomy and Aging,30 and a cohort using Swedish Health Care registers.31 Not all studies supported the association between surgical menopause and CHD. Contrary data emerged from analysis of the WHI observational study.19 In a 2011 analysis of the data, BSO was not associated with an increased risk of fatal or nonfatal CHD.19 The rate of HT use, however, was quite high, and 78.6% of women were identified as past or current users. The role of hysterectomy and oophorectomy on CHD may be time dependent, with proximity to natural menopause an important determinant. The degree of estrogen deficiency may also play a role in long-term risk, and may be partially, if not fully, mitigated by HT in the years that follow menopause. Cognitive functioning The “healthy cell bias” and the “critical time window” theories have emerged from investigations of Alzheimer disease, dementia risk, and cognitive functioning decline in relation to menopausal status at the time of oophorectomy.32 The
“healthy cell bias” theory suggests that estrogens are neuroprotective of healthy neurons, but accelerate degeneration of cells that have already undergone pathologic changes. The “critical time window” theory asserts that initiation of HT around the time of menopause can be beneficial, but if initiated in late menopause, can actually be deleterious. In one particular study, an increased risk of cognitive impairment or dementia was demonstrated in premenopausal women who underwent unilateral or bilateral oophorectomy, with a trend of increasing risk with younger age at the time of surgery. When ET was given until the age of 50 years, however, the association disappeared33 (Table 4). Similarly, the risk of death associated with neurological or mental disease was increased in women who underwent bilateral oophorectomy at age <45 years, although there was no association when women underwent bilateral oophorectomy at age >50 years.34 An increased risk of early-onset dementia (age <50 years), has been observed with younger age at hysterectomy and/or oophorectomy.35 Hysterectomy with BSO was associated with the greatest increased risk of dementia age <50 years. In a study specifically designed to assess whether HT can decrease the risk of dementia in women aged 65 years, there was no observed benefit to the initiation of HT in older postmenopausal women.36 In a study aimed at assessing the risk of Alzheimer disease and oophorectomy, earlier age of surgical menopause was associated with a steeper slope of cognitive decline, and a higher burden of Alzheimer disease neuropathology. Conversely, there were no such associations between age at natural menopause and either clinical or pathologic outcomes.37 Initiation of HT use within 5 years of menopause, and continued for at least 10 years, was associated with a decreased slope of decline in global function. When initiated 5 years after surgical menopause, there was no attenuation of the decline in cognitive functioning. In a separate study, oophorectomy after natural menopause was not identified as an important
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TABLE 2
Cancer risk, mortality, and oophorectomy Author Total cancer
Ovarian cancer
Breast cancer
Cohort
Major findings
Parker et al, 2013
Nurses’ Health Study
Higher mortality from total cancer associated with oophorectomy (HR, 1.16; 95% CI, 1.05e1.29)
Gaudet et al,23 2014
Cancer Prevention Study-II Nutrition
Lower risk of total cancer associated with hysterectomy and BSO (RR, 0.9; 95% CI, 0.85e0.96)
Altman et al,22 2016
Swedish Health Care registers Lower risk of total cancer associated with hysterectomy and BSO (HR, 0.92; 95% CI, 0.87e0.96) Same risk reduction observed with hysterectomy alone (HR, 0.93; 95% CI, 0.91e0.95)
Mytton et al,18 2017
English Healthcare Registries
Ovarian conservation associated with significantly lower rates of admission (HR, 0.83; 95% CI, 0.78e0.89) and death (HR, 0.54; 95% CI, 0.45e0.65) for any cancer
Jacoby et al,19 2011
Women’s Health Initiative Observational Study
Lower incidence of ovarian cancer with hysterectomy and BSO (0.02%) compared to hysterectomy alone (0.33%)
Parker et al,16 2013
Nurses’ Health Study
Decreased risk of ovarian cancer after hysterectomy with BSO (HR, 0.06; 95% CI, 0.02e0.17)
Chan et al,24 2014
Kaiser Permanente of Northern California
Decreased risk of ovarian cancer after hysterectomy with BSO (HR, 0.12; 95% CI, 0.05e0.28)
Parker et al,16 2013
Nurses’ Health Study
Lower risk of breast cancer with oophorectomy age <47.5 y
Robinson et al,28 2016
Carolina Breast Cancer Study
Premenopausal hysterectomy and BSO associated with reduced risk of breast cancer (OR, 0.60; 95% CI, 0.47e0.77)
Mytton et al,18 2017
English Healthcare Registries
Ovarian conservation associated with significantly increased rate of admission (HR, 1.34; 95% CI, 1.15e1.55), but significantly decreased rate of death from breast cancer (HR, 0.61; 95% CI, 0.39e0.94)
Women’s Health Initiative Observational Study
No significant difference in colorectal cancer risk observed with hysterectomy and BSO
Parker et al,16 2013
Nurses’ Health Study
Increased mortality from colorectal cancer in patients having undergone hysterectomy with BSO (HR, 1.49; 95% CI, 1.02e2.18)
Gaudet et al,23 2014
Cancer Prevention Study-II Nutrition
No statistically significant difference in colorectal cancer risk observed with hysterectomy and BSO
Luo et al,25 2016
Meta-analysis
Increased risk of colorectal cancer with hysterectomy and BSO (pooled RR, 1.22; 95% CI, 1.06e1.40)
16
Colorectal Jacoby et al,19 2011 cancer
Lung cancer
Segelman et al,26 2016 Swedish Patient Registry
30% Increased risk of colorectal cancer in women who underwent BSO (HR, 2.28; 95% CI, 1.33e3.91)
Mytton et al,18 2017
English Healthcare Registries
Ovarian conservation associated with significantly decreased rate of death from colon cancer (HR, 0.47; 95% CI, 0.25e0.88)
Koushik et al,27 2009
Population-based case-control Increased risk of lung cancer in women having undergone surgical menopause with BSO (OR 1.90; 95% CI, 1.18e3.06)
Jacoby et al,19 2011
Women’s Health Initiative Observational Study
No significant difference in lung cancer risk observed with hysterectomy and BSO
Parker et al,16 2013
Nurses’ Health Study
Increased risk of lung cancer mortality (HR, 1.29; 95% CI, 1.04e1.61) with oophorectomy
Gaudet et al,23 2014
Cancer Prevention Study-II Nutrition
No statistically significant difference in lung cancer risk observed with hysterectomy and BSO
Mytton et al,18 2017
English Healthcare Registries
Ovarian conservation associated with significantly decreased rate of admission (HR, 0.66; 95% CI, 0.48e0.91), and no difference in rate of death from lung cancer
BSO, bilateral salpingo-oophorectomy; CI, confidence interval; HR, hazard ratio; OR, odds ratio; RR, relative risk. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
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TABLE 3
Coronary heart disease risk, mortality, and oophorectomy Cohort
Deleterious effect of BSO
Colditz et al, 1987
Nurses’ Health Study
Yes
Increased risk of CHD after BSO in women who were never treated with HT (rate ratio, 2.2; 95% CI, 1.2e4.2) Use of HT in early postmenopausal period after BSO eliminated increased risk
Parker et al,15 2009
Nurses’ Health Study
Yes
Increased risk of CHD at all ages after BSO (HR, 1.17; 95% CI, 1.02e1.35) Greater increased risk observed after BSO age <45 y (HR, 1.26; 95% CI, 1.04e1.54) Greatest increased risk observed after BSO age <50 y, and not treated with HT (HR, 1.98; 95% CI, 1.18e3.32)
Rivera et al,30 2009
Mayo Clinic Cohort Study of Oophorectomy and Aging
Yes
Most dramatic increase in CHD mortality observed with BSO <45 y, either not treated with HT to age 45 y, or interrupted treatment age <45 y (HR, 1.84; 95% CI 1.27e2.68) No increase in CHD mortality when women were treated with HT until age 45 y
Ingelsson et al,31 2011
Swedish Health Care registers
Yes
Hysterectomy with BSO associated with 40% increased risk of CHD in women age <50 y (HR, 2.22; 95% CI, 1.01e4.83)
Jacoby et al,19 2011
Women’s Health Initiative
No
BSO not associated with increased risk of CHD in all-comers, or women who never used HT
Author 29
Major findings
BSO, bilateral salpingo-oophorectomy; CHD, coronary heart disease; CI, confidence interval; HR, hazard ratio; HT, hormone therapy. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
determinant of Alzheimer disease risk in older women.32 Taken together, the data on oophorectomy and surgical menopause support a deleterious effect of estrogen deficiency on cognitive functioning, which is both age and dose dependent. Global cognitive decline, dementia, and Alzheimer disease risk may share a common correlate with estrogen deficiency. HT may mitigate some of the neurologic effects of estrogen deficiency when continued until the natural age of menopause or initiated in the perimenopausal period. Postmenopausal oophorectomy and natural menopause do not appear to confer the same risk on cognitive functioning as surgical menopause.
Sexual functioning Hysterectomy, particularly when women are highly symptomatic, can be beneficial to sexual functioning. In the Maryland Women’s Health Study, there was widespread improvement in the percentage of women who engaged in sexual relations after hysterectomy.38 An
important finding, however, was that BSO was associated with anorgasmia 1 year postoperatively, and that each year of age increased the odds of not experiencing orgasms 1 year after hysterectomy by 7%. Some studies demonstrated a deleterious effect of BSO on sexual functioning,39-42 while others have not38,43,44 (Table 5). The results of many of these studies are difficult to interpret, given the varied use of HT.38,39 Reduced androgen levels may be associated with low libido and development of hypoactive sexual desire disorder (HSDD). The effects on sexual functioning are not just dependent on the absolute changes in hormone levels, rather there appears to be a complex relationship among abruptness of hormone loss, proximity to menopause, and use of HT. One population in which there is less controversy over the decision to proceed with BSO at a young age is women with known BRCA gene mutations or otherwise increased risk of ovarian cancer. In these women, hormone loss is abrupt, and HT initiation is varied. Two studies examined the
impact of BSO and HT on women undergoing risk-reducing oophorectomy. A large observational study of high-risk premenopausal women in The Netherlands45 compared women undergoing gynecologic screening with women undergoing prophylactic oophorectomy. Of those undergoing oophorectomy, 47% reported HT use. All 3 groups (screening, oophorectomy with HT, oophorectomy without HT) reported comparable levels of sexual functioning, but both users of HT and nonusers in the oophorectomy group reported significantly more sexual discomfort. Thus, in this population, HT did not appear to alleviate sexual discomfort. In a prospective evaluation of BRCA mutation carriers undergoing oophorectomy, the majority of women who were premenopausal at the time of surgery experienced a significant decline in sexual functioning, particularly decreases in the domains of desire and vaginal dryness.46 Women who were taking HT reported better sexual functioning than nonusers, but worse than presurgical levels. At 1 year
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TABLE 4
Cognitive functioning, mortality, and oophorectomy Author Imtiaz et al, 2014
Deleterious effect of BSO
Cohort 32
Bove et al,37 2014
Major findings
No All women with clinically verified AD, residing in Finland in 2005 91.8% of Women were age >51 y at time of BSO, therefore predominantly postmenopausal
Utilized information from national registries to determine if oophorectomy with or without hysterectomy is associated with AD risk No significant difference in relative risk of AD among women who underwent BSO and/or hysterectomy Concluded that surgery after natural menopause is not important determinant of AD risk
Participants from 2 longitudinal studies of cognitive decline 1/3 Previously undergone surgical menopause
Earlier age at surgical menopause was associated with steeper slope of global cognitive decline Earlier age at surgical menopause was associated with higher burden of AD neuropathology HRT use within 5 y of surgical menopause, for at least 10 y, was associated with decreased slope of decline in global cognition
Yes
Phung et al,35 Register-based historical cohort of 2010 Danish women Included women who underwent hysterectomy oophorectomy
Yes, but unclear effect Increased risk of dementia with hysterectomy of hysterectomy alone alone (RR, 1.38; 95% CI, 1.07e1.78), hysterectomy þ USO (RR, 2.10; 95% CI, 1.28e3.45), and hysterectomy þ BSO (RR, 2.33; 95% CI, 1.44e3.77)
Rivera et al,34 Participants of Mayo Clinic Cohort 2009 Study of Oophorectomy and Aging Women who underwent premenopausal oophorectomy
Yes
Increased risk of death associated with neurological or mental disease in women who underwent bilateral oophorectomy <45 y (HR, 5.24; 95% CI, 2.02e13.6) No association identified in women who underwent oophorectomy >45 y
Rocca et al,33 Participants of Mayo Clinic Cohort 2007 Study of Oophorectomy and Aging Women who underwent hysterectomy oophorectomy
Yes
Oophorectomy associated with increased risk of cognitive impairment or dementia, with trend of increasing risk with younger age at time of surgery Significantly increased risk when oophorectomy was performed age <49 y (HR, 1.70; 95% CI, 1.15e2.51), and HT not given through age 50 y
AD, Alzheimer disease; BSO, bilateral salpingo-oophorectomy; CI, confidence interval; HR, hazard ratio; HRT, hormone replacement therapy; HT, hormone therapy; RR, relative risk; USO, unilateral salpingo-ophorectomy.. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
postoperatively, there was a decline in sexual functioning regardless of HT use. HT did appear to alleviate the discomfort of surgical menopause, but the decline in sexual pleasure was unchanged. HSDD, presumably from an abrupt loss of androgens, has been linked to surgical menopause. The Women’s International Study of Health and Sexuality47,48 cross-sectional survey studied the prevalence of HSDD in surgically menopausal women. The data from the US48 and European47 cohorts yielded similar results as the percentage of women with HSDD was significantly higher in the young surgically menopausal population when compared to age-matched premenopausal women.
HT mitigates physical signs of genitourinary atrophy, but not necessarily key components of sexual functioning such as desire, orgasm, and satisfaction. BSO at any age confers a risk of HSDD, but is demonstrated most robustly in the population of women age <50 years at the time of surgery.
Osteoporotic fracture risk Osteoporosis and bone fracture risk play an important role in postmenopausal women’s health. Hip fracture in particular can result in increased mortality, as well as loss of mobility and need for long-term care.49,50 There is clear and convincing evidence that estrogen deficiency is associated with loss of bone mass, particularly when it occurs early in
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life. Current evidence suggests that 75% of bone loss occurs during the first 2 decades after menopause, and is attributable to estrogen deficiency, rather than aging.51 Bone mineral density (BMD) from loss of exogenous estrogen occurs much more rapidly than in menopause. A longitudinal observational study of >80,000 women evaluated the effects of HT cessation on bone loss.52 Longer duration of HT cessation was linearly correlated with lower BMD, and hip fracture risk significantly increased with longer duration of HT cessation. The protective association of HT with hip fracture disappeared within 2 years of cessation, demonstrating the absence of a durable long-term benefit.
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TABLE 5
Sexual functioning, hysterectomy, and oophorectomy Author
Cohort
Deleterious effect of BSO
Major findings
Chen et al, 2013
Yes Women aged 45e60 y Having undergone hysterectomy BSO Not given HRT
Utilized FSFI; score of <26 indicated sexual dysfunction More patients in hysterectomy-alone group scored >30, and women in that group recorded better scores in sexual performance, arousal, orgasm, satisfaction, pain, and vaginal lubrication No difference in sexual interest between groups
Rodriguez et al,40 2012
Sexually active women 1 y after Hysterectomy BSO for benign indications
No, but unclear effect of hysterectomy alone
Used FSFI; score of <26.55 indicated sexual dysfunction Mean score was 19.4, with all participants scoring <26.55 No difference in sexual functioning by oophorectomy status No difference in sexual functioning by HT status
Sozeri-Varma et al,41 2011
Women undergoing hysterectomy BSO
No
Evaluated measures of anxiety (Hamilton Anxiety Rating Scale), depression (Hamilton Depression Rating Scale), and sexual satisfaction (Golombok Rust Inventory of Sexual Satisfaction) at baseline, 3 mo, and 6 mo postoperatively No observed differences between patients by BSO status No observed differences between HRT status
Finch et al,46 2011
Women aged 30e70 y Undergoing risk-reducing BSO for known BRCA mutation
Yes
Utilized Menopausal-Specific Quality-of-Life questionnaire Majority of women who were premenopausal at time of surgery experienced decline in sexual functioning (decrease in sexual desire, vaginal dryness, and avoidance of intimacy) Women who were premenopausal at time of surgery, and used HT postoperatively, had better sexual functioning than those who did not use HT, but still worse than presurgical levels Women who were postmenopausal at time of surgery experienced small but statistically significant decrease in sexual functioning
Celik et al,43 2008
Postmenopausal women Undergoing TAH/BSO or TVH/BSO
Yes, but unclear Utilized FSFI Hysterectomy with BSO by either route resulted effect of in significantly reduces FSFI score at 6 mo hysterectomy postoperatively alone
Teplin et al,42 2007
Premenopausal women Participants of medicine or surgery trial, and total or supracervical hysterectomy trial
No
Utilized Medical Outcomes Study (MOS) Sexual Problems Scale No statistically significant difference in measures of sexual functioning by BSO status HT unexpectedly associated with worse outcomes
Yes
Utilized Profile of Female Sexual Function and Personal Distress Scale to determine prevalence of HSDD among US women Percentage of women aged 20e49 y who were surgically menopausal and distressed by their low desire (26%) was significantly greater than premenopausal women of similar age (14%) These results are despite fact that majority of women aged 20e49 y who were postmenopausal reported using estrogen therapy
44
Leiblum et al,48 2006 Surgically menopausal women aged 20e49 y Surgically menopausal women aged 50e70 y Premenopausal women aged 20e49 y Naturally menopausal women aged 50e70 y
Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
(continued)
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TABLE 5
Sexual functioning, hysterectomy, and oophorectomy (continued) Author
Deleterious effect of BSO
Cohort
Major findings
Same participant cohorts as Leiblum et al,48 2006
Yes
Utilized Profile of Female Sexual Function and Personal Distress Scale to determine prevalence of HSDD among European women Women of any age group who underwent bilateral oophorectomy were more likely to meet criteria for HSDD than their reproductive-aged counterparts Likelihood of experiencing low desire and HSDD was significantly less among HT users
Madalinska et al,45 2006
Premenopausal women at high risk of ovarian cancer Having undergone prophylactic BSO, with or without HT, or undergoing screening
Yes
Utilized Sexual Activity Questionnaire to measure sexual functioning Surgically menopausal women using HT, nonusers of HT, and women in screening group reported comparable levels of sexual functioning, but BSO groups reported significantly more sexual discomfort
Aziz et al,39 2005
Perimenopausal women aged 45e55 y Unclear Having undergone hysterectomy BSO
Utilized McCoy Female Sexuality Questionnaire to evaluate presurgical and postsurgical sexual functioning All oophorectomized women, and women with climacteric symptoms were encouraged to initiate HRT; therefore 98% of oophorectomized women and 23% of nonoophorectomized women initiated HT Hysterectomy-only group scored significantly higher on McCoy Female Sexuality Questionnaire, both preoperatively and postoperatively, when compared to participants undergoing hysterectomy with BSO Similar changes in scores were noted between groups, which was overall worse 1 y postoperatively
Rhodes et al,38 1999
Participants of Maryland Women’s Health Study Premenopausal and postmenopausal women undergoing hysterectomy BSO for benign conditions
Designed to measure outcomes and effectiveness of hysterectomy for benign conditions Frequency of sexual relations increased after hysterectomy Percentage of women experiencing dyspareunia dropped after hysterectomy Orgasm frequency increased after hysterectomy Women who underwent BSO were significantly more likely to be anorgasmic at 12 mo postoperatively
Dennerstein et al, 2006
47
Yes
BSO, bilateral salpingo-oophorectomy; FSFI, Female Sexual Function Index; HRT, hormone replacement therapy; HSDD, hypoactive sexual desire disorder; HT, hormone therapy; TAH, total abdominal hysterectomy; TVH, total vaginal hysterectomy. Adelman. Ovarian conservation. Am J Obstet Gynecol 2018.
What is less clear is the effect of oophorectomy on bone loss and fracture risk in older postmenopausal women. A statistically significant increase in fracture rate was observed in one study of women who underwent BSO after natural menopause.53 In fact, there was both an increase in the rate of traditional osteoporotic fractures, as well as fracture at any of the remaining skeletal sites. The loss of BMD that follows menopause is irrespective of whether it is
surgical or natural. HT may mitigate these losses, but the effect appears to be limited to the duration of use, with loss of benefit several years after cessation. There does, however, appear to be some protective effect of the postmenopausal ovary, perhaps due to the small production of androgens.
Subsequent surgery Decreased risk of subsequent surgery for ovarian pathology has been cited as one
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of the benefits of BSO at the time of hysterectomy. Recently, a study presented long-term follow-up with an agematched referent group to evaluate the cumulative incidence of subsequent oophorectomy in women who previously underwent hysterectomy with ovarian preservation.54 Nearly 5000 cases were compared to a similar number of referent women, with a median followup of approximately 20 years. The cumulative incidence of subsequent
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ajog.org oophorectomy was 3.5%, 6.2%, and 9.2% among case group participants at 10, 20, and 30 years, compared to 1.9%, 4.8%, and 7.3% among referent group participants. While the overall risk of subsequent oophorectomy among case group participants was significantly higher than among referent group participants (HR, 1.20; 95% CI, 1.02e1.42), the incidence of oophorectomy after hysterectomy at 30-year follow-up was only 1.9 percentage points higher than the incidence of oophorectomy in referent women with intact reproductive organs. We interpret this difference to be clinically insignificant, and as such, does not support the routine removal of ovaries for the purpose of avoiding future surgery.
Ovarian cancer prevention The Society of Gynecologic Oncology (SGO) released revised recommendations in 2015 for the prevention of ovarian cancer,55 which focused on the role of the fallopian tube as a conduit for retrograde menstruation, and a possible source of neoplastic epithelial cells. A recent paradigm shift in our understanding of the pathogenesis of ovarian cancer has led to the classification of type 1 tumors, which tend to present at earlier stages and are thought to arise from precursor lesions, and type 2 tumors, which tend to present at advanced stages and are thought to arise from neoplastic progression of fallopian tube epithelial cells. Type 1 tumors include low-grade serous, low-grade endometrioid, clear cell, and mucinous histology types. They are hypothesized to result from endometriosis, inflammation, uninterrupted and frequent ovulation, and the overall microenvironment, including reactive oxidative species. The morphologic, genetic, and molecular similarities of endometrioid and clear cell carcinomas with endometriotic cysts, has provided support for the hypothesis of retrograde menstruation and the derivation from the endometrium in those subtypes. Occlusion of the tubes should therefore decrease the risk of some type 1 tumors, and in fact, tubal ligation is associated with a 34% overall risk reduction in
ovarian cancer in women of average risk.56 Type 2 tumors include high-grade serous carcinomas, high-grade endometrioid adenocarcinomas, undifferentiated carcinomas, and carcinosarcomas. These cancers contain p53 mutations in an overwhelming majority of cases. In both BRCA1 and BRCA2 mutation carriers, as well as in sporadic cases of serous ovarian cancers, the p53 mutation identified in the ovarian tumor frequently matches mutations seen in precursor lesions of the fallopian tube. Salpingectomy would therefore be expected to reduce the incidence of type 2 ovarian cancers, as well as some type 1 ovarian cancers. The SGO has proposed several strategies aimed at the prevention of ovarian cancer, and include oral contraceptive use, tubal sterilization (which can include salpingectomy), and opportunistic salpingectomy at the time of pelvic surgery. Risk-reducing salpingooophorectomy is therefore reserved for women with high hereditary risk of breast and ovarian cancer.55 In Committee Opinion number 620, the American Congress of Obstetricians and Gynecologists proposes salpingectomy at the time of hysterectomy, or as a means of tubal sterilization, but cautions against a change in the approach of hysterectomy or sterilization, based solely on the benefits of salpingectomy.57
Conclusions There is a deleterious effect of oophorectomy on overall mortality, particularly when completed at age <50 years. While HTmay mitigate the increased mortality with oophorectomy, at no age does there appear to be a survival benefit. Based on Markov modeling, ovarian conservation may even confer a long-term survival benefit until the age of 65 years. There is a significantly lower rate of ovarian cancer observed after oophorectomy at all ages, and a decreased risk of breast cancer when oophorectomy is completed at age <47.5 years. The relationship between oophorectomy and all-site
cancer, colorectal cancer, and lung cancer is unclear, although most data favor a lower risk with ovarian conservation. The existing data do not universally implicate BSO in CHD, but there are no data that support a beneficial effect of oophorectomy on CHD. In aggregate, ovarian preservation is associated with an observed benefit to cardiovascular health. Global cognitive decline, dementia, and Alzheimer disease risk may share a common correlate with estrogen deficiency. Surgical menopause appears to confer a risk that is not observed with postmenopausal oophorectomy and natural menopause. BSO at the time of hysterectomy confers a deleterious effect on sexual functioning. HT mitigates physical signs of genitourinary atrophy, but not necessarily key components of sexual functioning, such as desire, orgasm, or satisfaction. BSO at any age confers a risk of HSDD. Estrogen deficiency following natural or surgical menopause is associated with BMD loss and increased fracture risk. HT can halt bone density loss, but the effect is limited to the duration of use, and significant losses can be observed within 2 years of cessation. Although the risk of subsequent surgery following BSO is decreased, this decrease is minimal and of questionable clinical significance. Current data do not support the routine removal of ovaries for the purpose of avoiding future surgery. In the absence of a genetic susceptibility mutation, tubal ligation, salpingectomy, and hysterectomy itself can provide ovarian cancer risk reduction to women of average risk, without the untoward effects of oophorectomy, and without the need for HT. -
REFERENCES 1. Jacoby VL, Vittinghoff E, Nakagawa S, et al. Factors associated with undergoing bilateral salpingo-oophorectomy at the time of hysterectomy for benign conditions. Obstet Gynecol 2009;113:1259-67.
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