Ovarian Conservation at the Time of Hysterectomy for Benign Disease

Clinical Obstetrics and GynecologyVol.50 / Number 2 / June 2007

Abstract

Benefits of The Postmenopausal Ovary

Our Study Design

Our Study Results

Comment

Criticisms and Answers

Conclusions

Abstract

Prophylactic oophorectomy when hysterectomy

: 78% ( 45 ~ 64 years old)

Ovary (after menopause)

: continues to produce androstenedione and testosterone

androgens estrone

Oophorectomy

: risk of coronary heart disease (CHD) and osteoporosis ↑↑

converted in fat, muscle, and skin

Cause of Death ovarian cancer - 14,000 / year heart disease - 490,000 / year within 1 year after hip fracture - 48,000 / year

Abstract

Study DesignPubMed and the Cochrane database

- the incidence of disease and mortality from conditions that seem to be related to ovarian hormones : CHD, ovarian cancer, breast cancer, stroke and hip fracture - data for death from all other causes

The model hypothetical cohort of 10,000 women undergoing hysterectomy and wh

o chose oophorectomy (vs. ovarian conservation) between the ages of 50 and 54 [without estrogen therapy(ET)], that by the time they reach age 80

women will have died from ovarian cancer < 47women will have died from CHD > 838 women will have died from hip fracture > 158

Abstract

the decision to perform prophylactic oophorectomy shoul

d be approached with great caution for the majority of women who are at low risk of developing ovarian cancer

Introduction the percentage of hysterectomies + bilateral oophorectomies

25% (1965)→ 55% (1999) (more doubled ) 78% : concurrent oophorectomy between ages 45 ~ 64

(recent data from the CDC show that)

Ovarian cancerdiagnose before it has metastasized : hardlate stage disease : associated with a high mortality relatively uncommon malignancy

(if women with known BRCA 1 or 2 germ-line mutations or

from high-risk families are excluded)

Table 1. Annual Incidence of ovarian cancer by age group

Cause of Death

ovarian cancer : 14,000 women, every year

lung cancer : 70,000 women

colon cancer : 28,000 women

breast cancer : 40,000 women

heart disease : 490,000 women

within 1 year after hip fracture : 48,000 women

Benefits of preserving ovarian function

risks of coronary heart disease (CHD) osteoporotic fracture

Introduction

Benefit of the Postmenopausal Ovary

Ovaries produce

reproductive years : estradiol, testosterone, androstenedione

after menopause : androstenedione, testosterone (until age 80)

androgens estrone

After oophorectomy, menopausal women

: significantly lower plasma levels of androstenedione and

testosterone than naturally menopausal women.

converted in fat, muscle, and skin

Benefit of the Postmenopausal OvaryOophorectomy - the risk of cardiovascular disease ↑↑

Oophorectomy after age 50

the risk of developing a first MI by 40% ↑ [relative ratio 1.4, confidence interval (CI) 1.0-2.0]

Hysterectomy with oophorectomy

an independent predictor of Framingham risk of myocardial

infarction or coronary death - Data from the Women's Health Initiative (WHI)

Autopsy in women with prior bilateral oophorectomy

more severe coronary atherosclerosis

earlier menopause (natural or surgical)

associated with more subclinical atherosclerosis

Benefit of the Postmenopausal Ovary

Oophorectomy - the risk of osteoporosis ↑↑

estrogens and androgens : bone resorption↓

androgens : bone formation ↑

postmenopausal state at the time of oophorectomy

: osteoporotic fractures > 54% than women with intact ovaries - One study found that after 16 years of follow-up (median)

≥ 60 years old

: 2-fold increase in mortality after low trauma hip fractures

Our Study Design

PubMed and the Cochrane database

Incidence of disease and mortality from 5 conditions

: related to ovarian hormones

- CHD, ovarian cancer, breast cancer, stroke and hip fracture

data for death from all other causes

articles that investigated the relative risk of developing these 5

conditions for generally healthy women having a hysterectomy with

either oophorectomy or ovarian conservation between the ages of

40 and 75.

Our Study Design

Risk of Ovarian cancer

After hysterectomy

: reduce by an average of 46%

< Theories to explain the decreased risk >

prohibiting reflux of carcinogens (endometrial tissue, HPV, or talc)

through the reproductive tract to the ovaries

destruction of reproductive tract tissue with release of antigens

cause the formation of antibodies (MUC 1) to ovarian cancer cells

After bilateral oophorectomy : 0%

Our Study Design

Risk of myocardial infarction

up to age 55

: double the baseline risk (relative ratio=2.2 CI 1.2-4.2)

ages 55 ~ 65

: the risk of CHD was found to decrease 6% for each year

oophorectomy is delayed after menopause

> 65 years old

: the relative risk of MI 1.0 (d/t no applicable data)

Our Study Design

Risk of osteoporotic fracture

after age 49

: 50% increased risk of hip fracture

after age 60

: 2-fold in mortality ↑ after low trauma hip fractures - a prospective cohort study (OR 2.18, CI 2.03-2.32)

60 ~ 64 : lost 11 years of life 70 ~ 74 : lost 4.4 years

after hip fracture

Our Study Design

Risk of breast cancer

age < 50

: 50% reduction in for 10 years after the surgery

age > 50

: no reduction in risk

Our Study Results

Figure I. Risk of death by age 80 for non-ET users as a function of age at oophorectomy with 95% confidence interval

Our Study Results

ages 50 to 54 with hysterectomy

- average risk of ovarian cancer, CHD, osteoporosis, breast cancer, and stroke the probability of surviving to age 80

ovarian conservation : 62.46%

oophorectomy : 53.88%

→ 8.58% difference in survival - fewer women dying of CHD (15.95% vs. 7.57%)

- hip fracture (4.96% vs. 3.38%)

age 55 ~59

- the survival advantage : 3.92%

after age 64

- no significant difference in survival

Our Study Results

Sensitivity analyses were performed and no analysis showed that oophorectomy

improved survival

Our Study Results

For a hypothetical cohort of 10,000 women undergoing hysterectomy

and who chose oophorectomy (vs. ovarian conservation) between the

ages 50 and 54 (without ET), our analyses predict that by the time

they reach age 80,

Ovarian cancer : < 47 women will have died

CHD : ≥ 838 women will have died

hip fracture : ≥ 158 women will have died

→ oophorectomy

: leads to an overall excess mortality of 858 / 10,000 women in this age group.

Comment

Heart disease : relatively common cause of death

Ovarian cancer : uncommon

→ benefit to ovarian conservation at the time of hysterectomy for

benign disease (not at high risk of ovarian cancer)

Comment

Oophorectomy

Age < 65 : the risk of dying from CHD ↑

Age > 65 : mortality primarily due to hip fracture ↑

in premenopausal, and some postmenopausal women

: lead to the sudden onset of hot flushes, mood disturbances

Other problems

- a decline in a sense of well-being

- a decline in cognitive functioning

- poor sleep quality, depression

- a decline in sexual desire

- frequency

Criticisms and Answers

I. Use of the Nurse's Health Study data (because it was observational)

→ study followed 121,700 women over 6 years and remains the

largest database available for analysis

II. opinion that we should not have included the oophorectomy and no ET arm in our study, because this choice should be unacceptable to gynecologists

→ clearly the most common situation found clinically

Criticisms and Answers

III. Oophorectomy be performed as prophylaxis for the future

possibility of pelvic pain, residual ovary syndrome, mild

endometriosis, or ovarian cyst formation

→ among 2561 women having a hysterectomy without oophorectomy

for any indication and followed for 20 years, subsequent

oophorectomy - performed in just 2.8%

Criticisms and Answers

IV. There were many risk factors for disease and mortality (menopausal status, age, lipoprotein patterns, gallbladder disease, venous thromboembolism and colon cancer, etc) that

our model did not take into account

→ we purposely constructed the model without too much

complexity by choosing the 5 conditions most commonly

associated with oophorectomy.

→ On the basis of our sensitivity analyses, it is unlikely that these

factors would influence the outcome of our study.

Criticisms and Answers

approximately 300,000 US women

: incidental oophorectomy annually

→ based on one factor alone - the risk and fear of ovarian cancer

: inappropriate

risk of ovarian cancer

: has been overemphasized by physicians to the exclusion of

other long-term risks of estrogen deficiency

raise awareness among women and their gynecologists regarding the public health consequences of routinely performed

oophorectomy.

Conclusions

Prophylactic oophorectomy

: approached with great caution for the majority of women

at low risk of developing ovarian cancer

< age of 65

“the decision to perform prophylactic oophorectomy : based on

the patient's age

other factors that weigh individual risk for developing ovarian cancer against loss of ovarian function.”

- recommended by Clinical management guidelines published by the American College of Obstetricians and Gynecologists in 1999 –

Next

Criticisms and AnswersIn 1999, before publication of the WHI, and “at a time when medical support for ET and publicity for ET were high,” only 31% of women continued to use ET for 5 years or longer after hysterectomy and oophorectomy. And, in the 6 months after publication of the WHI continuation rates of ET decreased from 12.6% to 9.1% and new starts also decreased significantly.In women with documented osteoporosis and beginning treatment with either ET, estrogen and progestin, bisphosphonates or raloxifene (n=58,109) medication continuation rates were less than 25% at 12 months.Likewise, statin continuation rates are 18% at the end of 1 year.

Criticisms and Answers

Women may have side effects, cost-related issues, or fears and belief systems about medications that preclude use despite a physician's recommendation. Furthermore, none of these studies account for women who never see a doctor, or who never get a prescription, or who get a prescription but choose not to fill it and they, therefore, underestimate the subsequent risk of untreated disease for large numbers of women. Consequently, the assumption that medical treatment can ameliorate these conditions after oophorectomy is not convincing.

Criticisms and Answers

V. “it is hard to believe that estrogens are more dangerous than conserved ovaries” and pleaded for oophorectomy.We wonder what ever happened to the concept of “evidence” and the principle “first, do no harm”?

Estrogens in women:In women, estrogens normally exist in approximately the following ratio:Estriol 60-80%Estradiol 10-20%Estrone 10-20%it was generally believed that the decreased incidence of CHD in women before menopause was mediated by a protective effect of estrogen on the coronary arteries, achieved by modulating levels of serum cholesterol.4 However, other research suggests that estrogen-induced improvements in serum cholesterol account for only one third of the observed clinical benefits of estrogen.It was hypothesized that an atheroprotective effect of estrogen may be mediated by this hormone’s direct effect on vascular smooth muscle cells.In fact, the data show that estrogen can increase dilation of arteries and inhibit the response of blood vessels to injury and the development of atherosclerosis.

relationship between androgen levels and CHD in women. The idea that DHEA protects against atherosclerosis was proposed by Kask in 1959. Some data show that serum dehydroepiandrosterone sulfate (DHEA-S) and androgen levels decline with age, and that levels in the normal physiological range are correlated with lower risk of carotid artery atherosclerosis. There is growing support for a possible benefit of DHEA supplementation in preventing cardiovascular events in women, predominantly through an estrogenic effect. Testosterone can regulate vascular physiology directly through stimulation of androgen receptors and inhibition of plaque formation, and indirectly after conversion to estradiol. Nevertheless, evidence concerning the efficacy of DHEA and testosterone in protecting the cardiovascular system remains inconclusive and warrants further study.

Our study has several weaknesses.The probability estimates were derived from mostly case-control studies, with the inherent weaknesses of selection bias, reporting bias, and chance. Our study combines the data from different studies and disparate populations, but to date no large cohort study has examined all of these outcomes in the same population.Subjects for most selected studies were predominantly white and further study is needed to confirm these estimates for non-white women.