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Date of release: 15 July, 2013

Differences in mortality between oophorectomy and ovarian conservation

A recent publication reported a study conducted by the Nurses' Health Study (NHS) which tried to compare the impacts of bilateral oophorectomy and of ovarian conservation in benign gynecologic cases where hysterectomy was carried out [1]. The research was a prospective 28-year, long-term observational study, which continued the analysis of the previous NHS research, already reviewed in 2008 with a follow-up period of 24 years. In the results of the first-stage research, it was concluded that bilateral oophorectomy during hysterectomy would decrease the risks of ovarian and breast cancer but, on the other hand, it would be accompanied by an increase in the incidences of coronary heart disease, stroke, lung cancer, total cancers, and mortality from all causes. The previous report also showed that, over a 24-year follow-up period, oophorectomy was associated with a 12% increase in all-cause mortality and significant increases in the risk of death from coronary artery disease (28%), lung cancer (31%), and all cancers (17%). The risk of death was the highest for women who had surgery before they reached 50 years old; they had a 40% increase in the risk of all-cause mortality. Oophorectomy was associated with a 28% increase in risk of death from coronary artery disease in all women, whether they used estrogens or not. The study also found that women who had oophorectomy without estrogen replacement had twice the risk of myocardial infarction compared with age-matched premenopausal women. The surgery was associated with an 85% increase in the risk of stroke in women who did not use hormones after menopause.
 
In the further analysis of updated data from the NHS, the authors focused on all-cause and cause-specific mortality and specifically examined bilateral oophorectomy compared with ovarian conservation in women aged 60 years or older to determine whether there was an age at which oophorectomy conferred a survival benefit. Subgroup analysis was also conducted in the women who, from the authors' hypothesis, would experience a more elevated mortality after bilateral oophorectomy, including women who underwent hysterectomy prior to age 50 years who never used estrogen therapy; women with known risk factors for cardiovascular disease; women with a family history of breast or ovarian cancer; and women who smoked. The aim of the study was to report long-term mortality after oophorectomy (n = 16,914) or ovarian conservation (n = 13,203) at the time of hysterectomy. The study was a prospective cohort study involving 30,117 participants in the NHS undergoing hysterectomy for benign disease. 
 
The result of the study showed that 2850 (16.8%) women with bilateral oophorectomy died from all causes compared with 1749 (13.3%) women who had ovarian conservation. Forty-four women with ovarian conservation and four with oophorectomy died from ovarian cancer over 28 years of follow-up (hazard ratio (HR) 0.06, 95% confidence interval (CI) 0.02–0.17). Oophorectomy was associated with higher mortality from coronary heart disease (multivariable HR 1.23, 95% CI 1.00–1.52), lung cancer (HR 1.29, 95% CI 1.04–1.61), colorectal cancer (HR 1.49, 95% CI 1.02–2.18), total cancers (HR 1.16, 95% CI 1.05–1.29), and all causes (HR 1.13, 95% CI 1.06–1.21). The results were not statistically different from any of the mortality outcomes when stratified by age at hysterectomy. The authors also found that, even though the number was insufficient to analyze some cause-specific deaths in women aged 60 years and older, the risk estimates associated with bilateral oophorectomy remained elevated for all-cause mortality, total cancer mortality, and cardiovascular disease mortality in these older women. Among women with hysterectomy prior to the age of 50 years, oophorectomy was associated with significant increases in risk of deaths from coronary heart disease, colorectal cancer, total cancers, and all causes. The conclusions of their research were that bilateral oophorectomy was associated with increasing mortality in women aged younger than 50 years old who had never used estrogen therapy and that oophorectomy was associated with increasing survival in no analysis or age group.

Comment

First, this NHS research showed the importance of ovarian conservation treatment especially before the age of 50 years. Some limitations were seen in the research design, including non-inclusion of diet and nutrition factors (lifestyle) as confounding variables, no review of the drugs consumed by the subjects such as statins, no consideration of environmental exposure, and limitation of its research population to just American-Caucasians (mostly White), which made it impossible to apply the research findings to other ethnic groups. On the other hand, although the research was observational in nature, it had enough power (n = 30,117) and was supported by a good data-recording system.
 
Second, it seems from the results that the choice of oophorectomy during hysterectomy treatment of benign gynecology cases is best not chosen until the women reach the age of 50 years. Ovarian conservation treatment becomes the best choice. It was also proven that the subjects using estrogen therapy (past and current users) would benefit because it would ameliorate the possibility of increasing risks of all-cause and cardiovascular disease mortality.
 
Third, because this research was observational in nature, it is necessary to conduct an identical research with a randomized clinical trial design in a long-term follow-up. More conclusive results would be obtained and these might be able to strengthen the meaning of this research result.
 
Fourth, users of estrogen therapy have decreased from 22% to 4% due to the publication of the results of the Women's Health Initiative which were blown up by the mass media; therefore, it is necessary to enlighten the press to the benefits of menopausal estrogen therapy based on these research findings. 
 
Last, other research on the same issue has shown inconsistent results caused by the small number of respondents, the short follow-up time, or taking as a comparison group women with natural menopause. For example, the British Menopause Society, through its press releases, has cited the statement that women below the age of 45 who are not given hormone replacement therapy following bilateral oophorectomy are at greater risk of mortality from several causes than age-matched women with their ovaries in place [2]. 
 
A study from the Mayo Clinic in the USA found that mortality from all causes increased 1.7 times for women in this age category and was particularly increased for estrogen-related cancers and diseases of the brain and cardiovascular system [3]. The study describes the follow-up of a small cohort of US women who had undergone unilateral (1293 women) or bilateral oophorectomy (1097 women) for non-cancer indications between 1950 and 1987, with 2390 controls. Although there was no overall significant difference in mortality between the groups, mortality was significantly higher in women who had received prophylactic bilateral oophorectomy before the age of 45 (HR 1.67, 95% CI 1.16–2.40). This increased mortality was seen mainly in women who had not received estrogen therapy and only became evident 10 or more years after oophorectomy. Deaths from hormone-related cancers and diseases of the brain or cardiovascular system increased by 1.6–6.0 times for these women compared with controls. The authors concluded that, although prophylactic bilateral oophorectomy undertaken before age 45 years is associated with increased mortality, it is uncertain whether it is causal or merely a marker of underlying risk.
 
Researchers from Canada have reported that women who have bilateral oophorectomy are 1.92 times as likely to develop lung cancer as women who have natural menopause [4]. On the other hand, a previous study from Japan found that either early age of menarche or early age of menopause was associated with a two-fold increased risk of developing lung cancer [5]. This study also found that women who took hormone replacement therapy for induced menopause had an even higher risk of lung cancer when compared with women with natural menopause without hormone replacement (relative risk 2.40). 
 
The current Canadian study [1] began as an evaluation of the possible association between the characteristics of menstruation and the development of lung cancer. The study involved 422 women with lung cancer and 577 matched controls. The researchers did not find any association between menstruation, pregnancy and lung cancer. However, they did observe that women who had bilateral oophorectomy had almost a two-fold increase in risk of lung cancer compared to women who had normal menopause. They also found an inverse relationship between age at menopause and risk of lung cancer. These authors speculated that hormonal factors related to early menopause increased the risk of developing lung cancer.
 
In conclusion, all the above studies suggest a complex role of endogenous and exogenous estrogen in a variety of diseases [6–8]. In relation to lung cancer, it is very possible that estrogen has a role in the immunology process. Therefore, decreasing estrogen levels during menopause might trigger a carcinogenetic process in the lung tissues.
 
The Canadian data [1] suggest that women who are not at higher than normal risk of ovarian cancer should not have bilateral oophorectomy performed for benign disease, since this significantly increases the risk of lung cancer and all-cause mortality, while the Japanese study [5] also suggests that hormone replacement therapy is not a good option for treating surgically induced menopause. For these reasons, it is necessary to conduct an identical long-term, follow-up study with a randomized clinical trial to obtain more conclusive results.

M. Sjarief Darmasetiawan


Senior Consultant of Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Gatot Soebroto Central Army Hospital, Faculty of Medicine of Pembangunan National Veteran University, Jakarta, Indonesia; Chairman of Board of Trustees of Indonesian Menopause Society (PERMI)



    References

  1. Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses Health Study. Obstet Gynecol 2009;113:1027-37.


    http://www.ncbi.nlm.nih.gov/pubmed/19384117

  2. Brown S. Press release. Further evidence in favour of HRT in early menopause. Menopause Int; November 2, 2006.


    http://www.thebms.org.uk/newsitem.php

  3. Shuster LT, Gostout BS, Grossardt BR, Rocca WA. Prophylactic oophorectomy in premenopausal women and long-term health. Menopause Int 2008;14:11116


    http://www.ncbi.nlm.nih.gov/pubmed/18714076

  4. Koushik A, Parent ME, Siemiatyck J, et al. Characteristics of menstruation and pregnancy and the risk of lung cancer in women. Int J Cancer 2009;125:242833


    http://www.ncbi.nlm.nih.gov/pubmed/19585503

  5. Liu Y, Inoue M, Sobue T, Tsugane S. Reproductive factors, hormone use and risk of lung cancer among middle-aged never-smoking Japanese women: a large-scale population-based cohort study. Int J Cancer 2005;117:662-6.


    http://www.ncbi.nlm.nih.gov/pubmed/15929081

  6. Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ 3rd. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006;7:821.


    http://www.ncbi.nlm.nih.gov/pubmed/17012044

  7. Rivera CM, Grossardt BR, Rhodes DJ, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause 2009;16:15-23.


    http://www.ncbi.nlm.nih.gov/pubmed/19034050

  8. Atsma F, Bartelink ML, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006;13:265-79


    http://www.ncbi.nlm.nih.gov/pubmed/16645540