Amenorrhea. A Case-Based, Clinical Guide

11. Long-Term Implications of Oophorectomy at the Time of Hysterectomy for Benign Disease

Donna Shoupe and Jonathan S. Berek 

(1)

Department of Obstetrics & Gynecology, Stanford University Hospital and Clinics, 300 Pasteur Drive Room HH333, Stanford, CA 94305-5317, USA

Jonathan S. Berek

Email: Jberek@stanford.edu

Abstarct

The National Center for Health Statistics report that in 2004, of the 617,000 ­hysterectomies performed in the USA, 73% also involved the surgical removal of the ovaries. In the United States, by age 60, about 1/3 of women undergo a hysterectomy [12]. Over the past decade, an average of 622,000 hysterectomies per year have been performed, and it is now estimated that there are 22 million women in the USA who have undergone this procedure [2]. According to the CDC, 52% of all hysterectomies are performed in women aged 44 years of age or younger. Of over 3 million hysterectomies performed between 1994 and 1999 in the USA, slightly over 10% were done for a primary diagnosis of cancer (Table 11.1). It is important to recognize the long-term implications of hysterectomy with and without oophorectomy and to counsel patients accordingly.

Introduction

The National Center for Health Statistics report that in 2004, of the 617,000 ­hysterectomies performed in the USA, 73% also involved the surgical removal of the ovaries. In the United States, by age 60, about 1/3 of women undergo a hysterectomy [12]. Over the past decade, an average of 622,000 hysterectomies per year have been performed, and it is now estimated that there are 22 million women in the USA who have undergone this procedure [2]. According to the CDC, 52% of all hysterectomies are performed in women aged 44 years of age or younger. Of over 3 million hysterectomies performed between 1994 and 1999 in the USA, slightly over 10% were done for a primary diagnosis of cancer (Table 11.1). It is important to recognize the long-term implications of hysterectomy with and without oophorectomy and to counsel patients accordingly.

Table 11.1

Estimated hysterectomy rates by age group and primary discharge diagnosis in the United States 1994–1999

Age

Cancer

Hyperplasia

Endometriosis

Leiomyoma

Prolapse

Other

15–29

13,193

 

53,663

12,312

17,173

165,120

30–34

20,318

3,533

106,575

69,836

47,816

87,806

35–39

29,246

8,026

156,330

222,206

77,818

103,526

40–44

36,906

13,792

143,718

399,277

80,342

69,542

45–54

64,802

44,990

136,060

553,641

126,851

72,132

>55

192,596

49,990

34,488

103,805

241,165

59,024

Total

360,197

121,651

630,834

1,361,786

593,619

457,150

Adapted from ref. [98]

Arguments for and Against Oophorectomy

One of the main arguments in the USA for bilateral oophorectomy at the time of hysterectomy for benign disease is to prevent the later development of ovarian cancer. While the overall lifetime risk of ovarian cancer is 1.4% among the U.S. women, the risk varies depending on the presence of risk factors. For white women with three or more term pregnancies and 4 or more years of oral contraceptive use, the risk of ovarian cancer by age 65 is only 0.3% compared to 1.6% among ­nulliparous women with no prior oral contraceptive use [3]. Other ­arguments for oophorectomy include decreasing the risk of subsequent ovarian pathology or ­adnexal pain that might require additional surgery. The reoperation rate in hysterectomized women for adnexal pathology is reported to be between 0.895 and 5.5% [46].

The chief argument against routine oophorectomy is that premenopausal oophorectomy leads to an abrupt decline in circulating estrogens and androgens, often leading to severe menopausal symptoms, including hot flashes, sleep disturbance, mood alteration, vaginal dryness, and sexual problems. Most importantly, oophorectomy has been associated with higher risks of coronary heart disease (CHD), hip fracture, Parkinsonism, dementia, cognitive impairment, visual declines, depression, and anxiety [78]. There is growing concern that the benefit of reducing a woman’s risk of ovarian cancer is outweighed by an increased risk of these serious diseases [911]

Long-Term Risks of Hysterectomy

The average age at menopause in women who have had an extrafascial hysterectomy and preservation of the ovaries is 3.7 years earlier than in women who have an intact uterus [12]. This is thought to be due to a decreased blood supply to the ovaries after hysterectomy. Multiple studies have also documented lower androgen levels [1315] and higher rates of bone loss in older hysterectomized women compared to nonhysterectomized women [1617]. A limited number of women report long-term adverse effects on sexual function after hysterectomy, including vaginal shortening or symptoms related to a loss of support to the bladder and bowel. However, improved sexual satisfaction and relief of bladder problems and improvements of bowel function are more commonly reported, especially in women with pain, bleeding problems or bowel or urinary problems prior to surgery. The loss of reproductive function may have emotional implications for a limited number of women.

Long-Term Risks of Oophorectomy in Premenopausal Women

Hot Flashes, Mood, and Quality of Life

Following bilateral oophorectomy in a premenopausal woman, the sudden loss of estrogen often triggers severe menopausal symptoms such as hot flashes, mood changes, headaches, reduced well-being, and sleep disturbances [1821]. Within a few years, other common problems associated with estrogen deficiency include vaginal dryness, painful intercourse, loss of sex drive, bladder dysfunction, poor sleep quality, and symptoms of depression also emerge [2225]. The severity of these symptoms and other estrogen deficiency-related problems are increased in oophorectomized women compared to naturally menopausal women, occur at an earlier age, and are usually more difficult to treat with hormonal therapy [21]. It is reported that more than 90% of premenopausal women will have vasomotor symptoms following oophorectomy [26].

Urogenital Atrophy

The loss of estrogen support for the bladder and vagina results in changes in lubrication, pH, normal bacterial flora, and tissue structure. Short-term symptoms associated with estrogen deficiency include decreased vaginal lubrication, itching, dryness, burning, and discharge. Long-term estrogen and possibly also androgen deficiencies lead to thinning of the vaginal epithelium and shrinkage of the tissues. Over time, these changes may result in fissures, ecchymoses, ulcerations, painful intercourse, pruritis, chronic inflammation, and vaginal stenosis. Changes in the urethral and bladder epithelium may cause a sensation of bladder pressure, urethral discomfort, dysuria, incontinence, urinary frequency, and recurrent urinary tract infections.

Oophorectomy, a predisposing factor leading to urogenital atrophy [2627] that increased the incidence of urogential atrophy is reported in surgically menopausal women compared to naturally menopausal women [2628]. This may be related to the low levels of androgens in oophorectomized women, as higher levels of androgens are reported to be protective [28].

Sexual Function

Oophorectomy in premenopausal women is often associated with a negative impact on sexual function. There is strong evidence that sexual desire and motivation in women are highly dependent on androgens [2930]. Additionally, androgens appear to impact on sexual sensation and orgasmic response. Studies report that following prophylactic oophorectomy, women with a high risk of hereditary ovarian cancer have significantly lower menopause-specific quality of life scores. In one study, 42–53% of the participants reported that their satisfaction with sexual functioning was moderately to extremely compromised [31]. In a similar study done in 846 high-risk women undergoing prophylactic oophorectomy, participants reported significant postoperative declines in sexual functioning and other endocrine ­problems [32].

Studies in normal risk women report no decline in sexual function following hysterectomy alone, but dramatic reductions following hysterectomy with oophorectomy. These declines in sexual function were reversed following estrogen and androgen therapy [22].

Central Nervous Effects: Cognitive Thought, Memory, Depression, Parkinson’s Disease

Premenopausal oophorectomy is reported to have significant effects on CNS function and is associated with declines in cognitive thought, memory, energy level, mood, and feelings of wellbeing [22253340]. Estrogen has been shown to be neuroprotective in animals and cell culture, [35] suppressing inflammation, reducing oxidative stress, improving synapse formation, upregulating neurotrophic factors, facilitating regeneration of vascular endothelium, [41] protecting dopaminergic neurons, reducing oxidative stress, and upregulating neurotrophic factors. Estrogen may act as an antioxidant, and appears to increase choline acetyltransferase activity and reduce deposition of amyloid [3542].

The Mayo Clinic Cohort Study followed women living in Minnesota who underwent either unilateral (n = 1,252) or bilateral oophorectomy (n = 1,075) for 25–30 years. These women were age matched to women (n = 2,368) who had not undergone oophorectomy. The results of this study reported that women who underwent either unilateral or bilateral oophorectomy prior to menopause and did not take hormone therapy had an increased risk of parkinsonism (HR 1.68; 95% CI 1.06–2.67), cognitive impairment or dementia (HR = 1.46; 95% CI 1.13–1.90), and anxiety (HR = 2.29; 95% CI 1.13–3.95) or depression (HR = 1.54 95% CI 1.04–2.26). The risk of each of these conditions increased with younger age at oophorectomy. The authors proposed that ovarian hormones have a neuroprotective effect [103637].

Osteoporosis and Hip Fracture

Both androgens and estrogens play important roles in normal bone metabolism as estrogens and androgens inhibit bone resorption and androgens stimulate bone formation [43]. Following oophorectomy in premenopausal women, increased bone turnover, and overall bone loss begins unless adequate hormone therapy is promptly started. Oophorectomy is considered an important risk factor for the development of osteoporosis and hip fracture [44]. After bilateral oophorectomy, women have significantly lower levels of androgens and estrogens compared to those who are naturally menopausal [144547]. Low levels of these hormones have been linked to lower bone density and increased the risk of hip fracture and vertebral fractures [14164852]. Unfortunately, hip and vertebral fractures are associated with increased morbidity and mortality [5354].

Quality of Life: Lens Opacities, Body Mass

Increases in macular degeneration and lens opacities are linked with early menopause [5556]. Oophorectomy adversely affects skin, body composition, and central adiposity [5761].

Cardiovascular Disease

Multiple observational studies report that women with surgical menopause have an increased risk of cardiovascular morbidity and mortality compared to women with natural menopause [786270]. Data from the Nurses’ Health Study (NHS) reported that oophorectomy between ages 40 and 44 doubled the risk of myocardial infarction (RR 2.2 95% CI 1.2, 4.2) compared to that of women with intact ovaries [771]. Even after age 50, oophorectomy increases the risk of developing a first MI compared to controls (RR 1.4, 95% CI 1.0–2.0) A published metaanalysis of observational studies found that oophorectomy doubled the risk of cardiovascular disease (RR 2.62 95% CI 2.05, 3.35) [8].

Other studies support the increased risk of cardiovascular disease following oophorectomy. Data from the Women’s Health Initiative (WHI) showed that hysterectomy with oophorectomy was an independent predictor of increased Framingham risk of myocardial infarction or coronary death [67]. Oophorectomy has been shown to increase serum lipids [7273], reduce carotid artery blood flow, [74] and have adverse effects on other atherosclerotic risk factors [7577]. Women having earlier menopause, as a result of bilateral oophorectomy, have more subclinical atherosclerosis compared to age-matched women who had natural menopause [78].

In a substudy of WHI placebo-controlled trial of conjugated estrogens, the authors aimed to determine the associations between coronary artery calcium (CAC) and hysterectomy, oophorectomy, and hormone therapy. CAC was measured by computed tomography in participants 1.3 years after the trial was stopped. Participants included 1,064 women with previous hysterectomy, aged 50–59 years at baseline. The mean trial period was 7.4 years. Imaging was performed at a mean of 1.3 years after the trial was stopped. The mean age was 55.1 years at ­randomization and 64.8 years at CAC measurement. There was a significant interaction between bilateral oophorectomy and prerandomization HT use for the presence of any CAC (p = 0.05). When multivariable analyses were restricted to women who reported no previous HT use, those with bilateral oophorectomy had an odds ratio of 2.0 (95% CI: 1.2–3.4) for any CAC compared with women with no history of oophorectomy, whereas among women with unilateral or partial oophorectomy, the odds of any CAC was 1.7 (95% CI: 1.0–2.8). Among women with bilateral oophorectomy, HT use within 5 years of oophorectomy was associated with a lower rate of CAC. The authors concluded that factors related to oophorectomy and the lack of estrogen treatment may be related to CHD [79].

Long-Term Risks of Oophorectomy in Postmenopausal Women

Hormone Production in the Postmenopausal Ovary

During the reproductive years, ovarian follicles secrete relatively large amounts of estrogens and androgens. During the menopausal transition, there is a loss of follicular activity and a resultant drop of estrogen, progesterone, and androgens. It is believed that the postmenopausal ovarian stromal tissues continue to produce substantial amounts of androgens and remain an important source of androgens for the remainder of a woman’s lifetime [45478082]. The peripheral conversion of these androgens to estrogens also provides low levels of circulating estrogens. Postmenopausal women with intact ovaries have significantly higher levels of plasma testosterone, androstenedione, and estrogens than oophorectomized women [454780] (Table 11.2). The benefits of postmenopausal ovarian androgens on bone and their derivatives and the consequences of their removal are well documented [45485052].

Table 11.2

Steroid hormone levels in natural vs. surgical menopause

 

Mean steroid levels in women (pg/mL)

Reproductive age (luteal phase)

Natural menopause

Surgical menopause

Estradiol

150

10–15

10

Testosterone

400

290

110

Progesterone

12,000–20,000

<100

<100

Adapted from refs. [4547]

In a cross-sectional study in 684 postmenopausal women ages 50–89 in a community-dwelling postmenopausal women, both total and bioavailable testosterone levels were 40% lower (p < 0.001) in hysterectomized women with bilateral oophorectomy compared to those in intact women. Women with ovarian conservation and hysterectomy had intermediate levels. Total estradiol levels tended to be lower (p = 0.095) in ­bilaterally oophorectomized women. Interestingly, among intact women, total testosterone levels increased with age (p = 0.015) peaking in the 70s to premenopausal levels and there on remaining relatively stable. Among intact women, total, but not bioavailable, testosterone levels increased with age (p = 0.015), reaching premenopausal levels for the 70–79 decade with relatively stable levels thereafter. The authors concluded that the postmenopausal ovary remains a critical source of androgen throughout the lifespan of older women. They suggested that reconsideration of prophylactic oophorectomy and further study of the effects of androgen replacement after oophorectomy are needed [14].

Controversies on Postmenopausal Ovarian Enzyme Activity

Despite a large body of research studies demonstrating substantial production of androgens from postmenopausal ovaries, [45478084] controversy remains regarding steroidogenic enzyme expression in the postmenopausal ovary. Investigators have demonstrated gonadotropin binding sites in the postmenopausal ovary, [8586] responsiveness to gonadotropins, [87] and decreases in serum androgen levels after postmenopausal women are treated with GnRH agonists [88]. Studies in women with endometrial hyperplasia or cancer, demonstrated by northern analysis that the postmenopausal ovary possesses all the enzymes necessary for androgen synthesis [89]. However, in a well-known study of ovarian steroidogenic enzymes by immunohistochemistry, the authors reported that the postmenopausal ovary lacked aromatase. They also reported that the enzymes necessary for ovarian androgen synthesis were detected very weakly and were scattered in hilar cells [90].

Recently, more sensitive detection methods have been used to determine the steroidogenic enzymes expressed in the human postmenopausal ovary. Real-time RT-PCR detected the presence of steroidogenic acute regulatory protein transcripts, cholesterol side-chain cleavage transcripts, 3β-hydroxysteroid dehydrogenease type II transcripts but undetectable 17α-hydroxylase transcripts [91]. In another study using microarray analysis and real-time RT-PCR, the authors reported that the postmenopausal ovary retained the ability to produce androgens with a unique pattern of steroidogenic enzyme expression [92].

Osteoporosis and Hip Fracture

For many years, oophorectomy prior to age 45 or early menopause has been ­considered an important risk factor for the development of osteoporosis and hip fracture [5093]. Less well appreciated, however, are the studies linking oophorectomy done in older, postmenopausal women to osteoporosis risk. In a 16-year study tracking 340 postmenopausal women, those elderly women undergoing an oophorectomy for benign conditions had 54% more osteoporotic fractures than those with intact ovaries [50]. The authors’ findings support the hypothesis that androgens produced by the postmenopausal ovary are important and protect against fracture risk.

In a related study investigating the effect of oophorectomy in postmenopausal women on bone metabolism, investigators measured serum and urinary markers of bone resorption and bone density in 80 menopausal women divided into 4 groups as follows: ≤3 years since natural menopause; ≥3 years since natural menopause; ≤3 years since oophorectomy; ≥3 years since oophorectomy. Lumbar BMD was lowest in the groups ≥3 years since oophorectomy. Serum markers of bone resorption were significantly higher in the early postoophorectomy group compared to all other groups. The authors concluded that women are at the greatest risk of bone resorption during the first few years following oophorectomy and that bone loss following oophorectomy is greater than that seen following natural menopause [51].

Quality of Life

Removal of ovaries in postmenopausal women usually results in the minimal change in estrogen levels and will rarely trigger the onset of hot flashes or other estrogen deficiency symptoms. However, there is generally a substantial effect on circulating androgen levels [4648], and the impact of this change may not be appreciated for many years. Androgens protect bone and muscle mass and affect the distribution of muscle mass, percent body fat, and skin thickness. A lack of these hormones, over many years, is believed to result in muscle loss, weakness, increased body fat, and skin changes.

Examining the Effect of Oophorectomy on Overall Mortality

Several analyses have been done to look at the overall survival impact of oophorectomy. In one of these, a decision analysis was performed using survival information from previously published observational studies. That analysis found that ovarian conservation maximized the survival for healthy women aged 40–65 (without a family history of ovarian cancer) who have a hysterectomy for benign disease. Women having had a hysterectomy at age 55 or younger with ovarian conservation had a 8.6% survival advantage over women with oophorectomy. There was never a survival benefit for removing ovaries in any age group [9].

A study from the Mayo Clinic found that mortality was not increased overall in women who underwent bilateral oophorectomy compared with referent women. However, mortality was significantly higher in women who had prophylactic bilateral oophorectomy before the age of 45 years and had not received estrogen up to the age of 45 years (HR 1.67, 95% CI 1.16–2.40). Specifically, mortality for neurological or mental disorders was significantly increased [10].

In a third study, NHS cohort database was analyzed, which included 122,700 married registered nurses ages 30–55 years in 1976 when the initial questionnaires were mailed. A total of 29,380 hysterectomized women were included in the analysis; 13,035 (44.4%) had a hysterectomy alone (ovarian conservation) and 16,345 (55.6%) with hysterectomy with bilateral oophorectomy. During the 24 years of follow-up through 2002, nonfatal events and death due to the CHD, stroke, breast cancer, epithelial ovarian cancer, lung cancer, colorectal cancer, hip fracture, pulmonary embolus, and death due to all causes were tabulated. Each outcome analysis was adjusted for multiple-related risk factors. Oophorectomy was associated with an increased risk of CHD for all women (HR 1.17 95% CI 1.02, 1.35) and was greater for women with oophorectomy before age 45 (HR 1.26 95% CI 1.04, 1.54). Breast cancer was less frequent among all women with oophorectomy (HR 0.75 95% CI 0.68, 0.84), and the risk was lower among women having oophorectomy before the age of 45 (HR 0.62 95% CI 0.53, 0.74). Oophorectomy was associated with a very low risk of ovarian cancer (HR 0.04; 95% CI, 0.01–0.09) and a slight reduction in total cancers (HR 0.90 95% CI 0.84, 0.96), but an increased risk of lung cancer (HR 1.26; 95% CI, 1.02–1.56) [11].

Controversies on Hormone Replacement

For most of the studies, the long-term effects of oophorectomy are mitigated in women taking hormone replacement therapy for extended periods of time. In the study mentioned above, for oophorectomized women without hormone therapy, the risks of stroke (HR 1.85 95% CI 1.09, 3.16) and lung cancer (HR 2.09 95% 1.01, 4.33) were significantly higher. For women having oophorectomy before age 50 without hormone therapy, the risk of incident CHD (HR 1.98 95% CI 1.18, 3.32) was higher and the risk of death from all causes was higher (HR 1.40 95% CI 1.01, 1.96) [11].

These data, along with the many studies, supporting the use of hormone replacement in women appear to be at odds with the findings of WHI that reported an absolute excess risk of 8 more strokes per 10,000 person-years attributable to estrogen plus progestin treatment [94]. However, the data above taken from the observational cohort of NHS, represent real life hormone use that typically begins at in early menopause with the onset of hot flashes. In order to better define the risks of starting hormone therapy in early menopause, several subsequent publications of the WHI divided the study group into 10-year age groups based on age or years since menopause. These studies reported that the age of initiation of therapy had a profound effect on the risk of cardiovascular events. One of these studies, reported that for women treated within 10 years since their menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval (CI), 0.50–1.16). For those treated 10–19 years, the HR was 1.10 (95% CI, 0.84–1.45) and for 20 or more years, the HR was 1.28 (95% CI, 1.03–1.58) (p for trend = 0.02) [95]. In another of these studies, the authors found no increase risk of stroke if estrogen was started between the ages of 50 and 59 [96].

Oophorectomy increased the risk of death from any cause (HR 1.12 95% CI 1.03, 1.21). Analysis of cause-specific mortality found an increased risk of death from CHD (HR 1.28, 95% CI 1.00, 1.64), lung cancer (HR 1.31, 95% CI 1.02, 1.68), and all cancers (HR 1.17, 95% CI 1.04, 1.32) and no overall difference in deaths from stroke, breast cancer, or colorectal cancer. While there was a reduced risk of death from ovarian cancer (HR 0.06; 95% CI, 0.02–0.21), during the 24 years of follow-up only 34 (0.7%) women died from ovarian cancer. At no age did oophorectomy show an overall survival benefit [11].

These data together would support the concept that there is an optimum therapeutic window for the initiation of estrogen therapy and that beginning estrogen during this window allows for the most benefit and lowest risk and may indeed offer substantial protection from cardiovascular ­disease [7997].

Conclusions

The purpose of prophylactic surgery is to provide a health benefit to patients. There is growing evidence that oophorectomy in many, if not most, women is associated with more risk than benefit (Table 11.3). Unless well-designed prospective, randomized studies can demonstrate clearly those women who will benefit, removing the ovaries at the time of hysterectomy should be approached with caution. For women without a genetic mutation or family history of ovarian cancer, current practice suggests that prophylactic oophorectomy is generally not beneficial for women under age 40–45 but recommendations vary greatly for ages 45 and older. It is important that both women and their healthcare providers consider the most reliable evidence regarding the potential risks and benefits of prophylactic oophorectomy in order to make appropriate decisions.

Table 11.3

Risks linked to oophorectomy

Body composition changes

Increase in adipose tissue and decreased muscle mass

Fat accumulation in central, abdominal area

Cardiovascular disease

Adverse effects on lipids and other risk factors

Increased rates of myocardial infarction

Accelerated atherosclerosis

Increased mortality

CNS

Short-term memory declines

Dementia

Decreased wellbeing

Parkinson’s disease

Len opacities and macular degeneration

Menopausal symptoms

Osteoporosis and fractures

Accelerated bone loss

Increased risk of hip and spinal fracture and associated morbidity and mortality

Sexual dysfunction and loss of desire

Skin changes

Loss of collagen, thinning, wrinkling

Urogenital atrophy

Bladder and vaginal symptoms

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