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 doi: https://doi.org/10.1136/bmj.j372 (Published 06 February 2017) Cite this as: BMJ 2017;356:j372All rapid responses
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April 18, 2017
To the BMJ Editor:
With regard to the report by Mytton and colleagues:
Mytton et al in an extensive retrospective study reported that women who had hysterectomy with ovarian conservation had a significantly lower risk of all-cause mortality and mortality from ischemic heart disease and cancer (1). They noted that removal of both ovaries protects against ovarian cancer while increasing the risk of cardiovascular mortality. Their observations contradict a detailed report of a cohort of 2873 Framingham Study female participants prospectively followed for 24 years (2). The 1978 study provided prospective evidence that menopause associates with a highly significant two-fold increase in the incidence of heart disease. Detailed data from the older study showed that cardiovascular protection diminished after surgical menopause regardless of whether or not oophorectomy had been performed.
Recently, Muka et al reported an overall higher mortality rate in women who experience premature or early on-set menopause and notably a higher risk of cardiovascular disease mortality for these women (3). However, postmenopausal women on hormones had a doubled risk of coronary heart disease.
We suggest that observed considerable increases in serum ferritin levels at menopause marks a dramatic shift in iron metabolism possibly linked to increased iron stores or with heightened inflammatory responses (4). We invite investigators to consider that the observed significant increased risk of cardiovascular disease in postmenopausal women is associated with altered iron homeostasis and potential increase in body iron stores after menstrual blood flow cessation (4).
The hypothesis that increased cardiovascular disease results from oxidative stress catalyzed by excess iron accumulation was tested in the VA Cooperative Study Trial 410, The Iron and Atherosclerosis Study (FeAST). The effects of phlebotomy on clinical outcomes were tested in peripheral arterial disease (PAD) with iron store reduction, estimated by serum ferritin; to levels approaching 25 ng/mL as occur in healthy menstruating women (5). Data from this prospective randomized study demonstrated that lower ferritin levels (76-78 ng/mL) predicted improved outcomes in younger men with (PAD) upon removal of an amount of iron represented by approximately a liter of blood. Lower ferritin levels strongly predicted improved clinical outcomes, regardless of randomization group, with a threshold for benefit below 76-78 ng/mL.
The striking relationship between menopause, whether surgical with or without oophorectomy, or natural, and coronary disease risk needs clarification. Dramatic changes during menopause in iron metabolism and hormone levels require prospective, granular studies to better understand and characterize the complex relationships seen during this transition. One possibility is that iron in catalytic form stimulates inflammatory responses and leukocyte activity and associates with elevation of IL-6 and other inflammatory biomarkers based on our findings of direct associations (6) between elevated ferritin and inflammatory biomarkers, predominantly IL 6, and mortality.
Data from multiple sources support a need for additional studies testing the relationship between increased cardiovascular disease risk related to changing iron homeostasis, the role of inflammation and hormone status in women during and after surgical or natural menopause. Additionally, Gordon et al (2) reported an alteration in lipid metabolism with cessation of menses, most evident with bilateral oophorectomy plus hysterectomy, and may supply insight into metabolic changes prompting increased cardiovascular disease risk. We recommend prospective serial measurements hormone replacement therapy (HRT) with estrogen and progestin or with estrogen alone, along with serial measures of hormone levels, lipid panels, ferritin, iron, hepcidin and inflammatory biomarkers in pre and postmenopausal women to better understand unique factors contributing to increased cardiovascular mortality. (4). Better understanding of the biological basis for menopausal effects on cardiovascular disease offers important insights into prevention and treatment of cardiovascular disease generally.
Respectfully,
Virginia W Hayes, MS, APN, BC: VA Sierra Nevada Health Care System, Reno Nevada
Ralph G DePalma, MD: VA Office of Research and Development, Washington, DC
Leo R Zacharski, MD; VA White River Junction Health Care System, White River, Vermont.
The authors are employees of the Department of Veterans Affairs and report no financial conflicts or interests. The opinions expressed are those of the authors and not necessarily those of the Veterans Administration or the Government of the United States.
1. Mytton J, Evison F, Lilford, LJ. 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 linkageBMJ 2017;356:j372
2. Gordon, T, Kannel WB, Hjortland, C, McNamara PM. Menopause and the risk of cardiovascular disease. The Framingham Study. Ann Intern Med 1978; 89 (2): 157-161
3. Muka T, Oliver-Williams C, Kunutsor S, et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: A systematic review and meta-analysis. JAMA Cardiol 2016; Sep 14: oi:10.1001/jamacardio.2016.2415
4. Hayes VW, DePalma RG, and Zacharski LR. Menstrual suppression, iron homeostasis, and disease risk. The Journal for Nurse Practitioners 2011; 7 (8): 660-664
5.. Zacharski LR, Shamayeva G, Chow, BK. Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial Disease. Am Heart J 2011; 162: 949-957.
6. DePalma RG, Hayes VW, Chow BK, Shamayeva G, May PE, Zacharski LR. Ferritin levels, inflammatory biomarkers, and mortality in peripheral arterial disease: A sub study of the Iron (Fe) and Atherosclerosis Study (FeAST) Trial. J Vasc Surg. 2010; 51(6): 1498–1503.
Competing interests: No competing interests
Dear Sir,
With regard to the report by Mytton and colleagues:
Firstly; there appears to be errors in Tables 3 and 4 with ovarian cancer rates higher in patients who have had hysterectomy with bilateral oophoectomy than in patients who had their ovaries conserved.
Secondly; I agree with the comments by Savvas and colleagues in relation to hormone replacement therapy (HRT) and would like to add in regard to bowel cancer; the protective effect of oestrogen HRT on bowel cancer are well described (2000). So the significant (p<0.001) increase in bowel cancer in the oophorectomised women may not occur if oestrogen HRT is administered.
References:
Mytton J, Evison F, Chilton P, Lilford R. 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.
Savvas M, Modares M, Ho W-L. Re: 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; 01 March.
Prihartono N, Palmer JR, Louik C, Shapiro S, Rosenberg L, A case-control study of use of postmenopausal supplements in relation to the risk of large bowel cancer. Cancer Epidemiology Biomarkers Prev 2000; 9:443-7.
Competing interests: No competing interests
We agree with the points made by Savvas and colleagues. We too suspect that oestrogen has a protective effect against heart disease – and said so in our discussion. We have also speculated that the increased heart attack rate observed with oestrogen replacement therapy in the trials mentioned, might have been because the hormone replacement therapy (HRT) was started many years after the menopause in most women in these studies.
We were thus a little surprised and disappointed to have our study described as ‘flawed’. The writers do not point to a design flaw, save that we did not have data on use of HRT. But we had already mentioned this was a limitation of our study – the study simply was not designed to find out whether HRT could obviate the increased risk of heart disease associated with ovary removal. The writers conflate a study limitation with a flawed study.
Competing interests: No competing interests
Dear Sir,
Mytton and colleagues confirm that oophorectomy in women between the ages of 35 and 45 is associated with a reduction in the incidence of ovarian cancer but that women should be warned that this benefit comes at a cost of increased heart disease and all-cause mortality. We believe this conclusion is flawed because of the absence on data on the use of HRT. The authors suggest that these results present a pragmatic association between surgical type and outcome irrespective of whether women take hormonal therapy or not.
The period studied followed the flawed 2002 WHI studies which reported an increase in breast cancer and heart disease in women taking HRT and resulted in a dramatic reduction in use of HRT. Subsequent reanalysis of the WHI studies have confirmed that unopposed oestrogen is not associated with an increased risk of breast cancer or heart disease and if started before the age of 60 may be protective. Despite these more positive findings many doctors especially those who trained after the publication of the WHI feel that hormonal therapy should be avoided or at least prescribed for the shortest duration possible. It is very likely, therefore, that in the population studied, many of the women were not taking hormonal therapy or at least were not taking it for a significant period of time.
Women who have had a hysterectomy should be prescribed unopposed oestrogen, thus avoiding progestogenic side effects and if the transdermal route is used, it will not increase the risk of thrombosis. Such therapy is not only safe but will control menopausal symptoms, improve quality of life and may reduce the incidence of breast cancer and heart disease.
We feel that when the ovaries are removed, hormonal therapy should be strongly advised and it is the responsibility of the surgeon to stress the importance of hormonal therapy to the woman and support her in continuing with this therapy.
While this study is useful in reminding us of the risks associated with oestrogen deficiency the findings are incomplete and do not provide useful information to help in counselling women as to whether or not to have bilateral oophorectomy at the time of hysterectomy. Women who are prematurely menopausal, whether iatrogenic or natural, should be encouraged to take hormonal therapy at least until the age of the natural menopause (51 years of age).
When advising women of the risks and benefits of oophorectomy in this age group, they should be advised that oopherectomy will protect against ovarian cancer as shown by this and other studies. They should also be alerted to the increased risk of heart disease and all-cause mortality secondary to oestrogen deficiency if HRT is not taken but that the use of HRT is safe, will prevent symptoms and avoid the long term risks of oestrogen deficiency.
References:
Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288(3): 321-333.
Hamoda H, Panay N, Arya R, Savvas M. The British Menopause Society & Women’s Health Concern 2016 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health 2016; 22(4): 165-183.
Mytton J, Evison F, Chilton P, Lilford R. 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.
Competing interests: No competing interests
It is interesting that Mytton and colleagues found that patients who had at least one ovary conserved had a significantly lower rate of all cause mortality than patients who had both ovaries removed.1 Was the increased mortality from cancers and heart disease because women who had bilateral oophorectomies are more likely to be given HRT?
2 Mytton J, Evison, 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.
Competing interests: No competing interests
Dear Editors,
Tibolone prevents postmenopausal bone loss and osteoporotic fractures better than raloxifene, as effectively as estrogens. [1][2][7]
Tibolone does not increase the risk of myocardial infarction. Indeed, it could have a beneficial effect. [3][7][15]
Tibolone reduces blood pressure, inflammation and glycaemia without worsening oxidative stress. [9]
Tibolone greatly reduces Lp(a) CVD risk factor. [14][17]
Tibolone does not increase the risks for thromboembolic events. In fact, tibolone influences coagulatory factors in menopause promoting fibrinolisis, even better than estradiol. [4][13]
Tibolone reduces the incidence of primary breast cancer and the risk for invasive breast cancer. [2][4][16]
Tibolone reduces visceral fat. [5][10]
Tibolone use decreases gout in postmenopausal women. [18]
Tibolone use decreases depression in postmenopausal women. [20]
Tibolone increases vitamin D3 levels in postmenopausal women. [19]
Tibolone improves almost all hearing threshold levels. [6]
Tibolone relieves climacteric symptoms, improves mood, improves sexual well-being (desire, arousal and orgasm domains), health-related quality of life. [7][8][11][19]
Tibolone also has in vitro antiproliferative effects! [12][21]
Those young hysterectomized and oophorectomized women who entered surgical menopause abruptly were ideal candidates for tibolone supplementary use.
Comparative results in this study might have been different, if proper supportive treatments were administered to ALL patients.
Ethics Commitees should also care to investigate if in the past eventual abandoning 35-45 year old ovariectomized/hysterectomized women without ANY pharmacological treatment was bad medicine.
Finally, due to surgical removal of incoming uterine vascularization and adherence issues, most remnant ovaries atrophy prematurely, as well.
References
[1] http://www.ncbi.nlm.nih.gov/pubmed/18256777
[2] http://www.ncbi.nlm.nih.gov/pubmed/18703472
[3] http://www.ncbi.nlm.nih.gov/pubmed/18826989
[4] http://www.ncbi.nlm.nih.gov/pubmed/19920271
[5] http://www.ncbi.nlm.nih.gov/pubmed/21872859
[6] http://www.ncbi.nlm.nih.gov/pubmed/20690865
[7] http://www.ncbi.nlm.nih.gov/pubmed/20586550
[8] http://www.ncbi.nlm.nih.gov/pubmed/20570264
[9] http://www.ncbi.nlm.nih.gov/pubmed/20500110
[10] http://www.ncbi.nlm.nih.gov/pubmed/19848555
[11] http://www.ncbi.nlm.nih.gov/pubmed/19731119
[12] http://www.ncbi.nlm.nih.gov/pubmed/19531283
[13] http://www.ncbi.nlm.nih.gov/pubmed/19349712
[14] https://www.ncbi.nlm.nih.gov/pubmed/28032426
[15] https://www.ncbi.nlm.nih.gov/pubmed/27733017
[16] https://www.ncbi.nlm.nih.gov/pubmed/26582062
[17] https://www.ncbi.nlm.nih.gov/pubmed/26186655
[18] https://www.ncbi.nlm.nih.gov/pubmed/25968834
[19] https://www.ncbi.nlm.nih.gov/pubmed/25482436
[20] https://www.ncbi.nlm.nih.gov/pubmed/15970290
[21] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874819/
Competing interests: No competing interests
Contradictory Findings During Menopause
April 20, 2017
To the BMJ Editor:
With regard to the report by Mytton and colleagues:
Mytton et al in an extensive data linked retrospective study reported that women who had hysterectomy with ovarian conservation exhibited a significantly lower risk of all-cause mortality and mortality from ischemic heart disease and cancer (1). They noted that removal of both ovaries protects against ovarian cancer while increasing the risk of cardiovascular mortality. Their observations contradict a detailed report of a cohort of 2873 Framingham Study female participants prospectively followed for 24 years (2). The 1978 study provided prospective evidence that menopause associates with a highly significant two-fold increase in the incidence of heart disease. Detailed data from the older study showed that cardiovascular protection diminished after surgical menopause regardless of whether or not oophorectomy had been performed.
Recently, Muka et al reported a higher risk of cardiovascular disease mortality and an overall mortality in women who experience premature or early on-set menopause (3). However, postmenopausal women on hormones had a doubled risk of coronary heart disease.
We suggest that observed considerable increases in serum ferritin levels at menopause marks a dramatic shift in iron metabolism possibly linked to increased iron stores or with heightened inflammatory responses (4). We invite investigators to consider that significantly increased risk of cardiovascular disease in postmenopausal women associates with altered iron homeostasis and potential increase in body iron stores after menstrual blood flow cessation (4).
The hypothesis that increased cardiovascular disease results from oxidative stress catalyzed by excess iron accumulation was tested in the VA Cooperative Study Trial 410, The Iron and Atherosclerosis Study (FeAST). The effects of phlebotomy on clinical outcomes were tested in peripheral arterial disease (PAD) with iron store reduction, estimated by serum ferritin; to levels approaching 25 ng/mL as occur in healthy menstruating women (5). Data from this prospective randomized study demonstrated that lower ferritin levels (76-78 ng/mL) predicted improved outcomes in younger men with (PAD) upon removal of an amount of iron represented by approximately a liter of blood. Lower ferritin levels strongly predicted improved clinical outcomes, regardless of randomization group, with a threshold for benefit below 76-78 ng/mL.
The striking relationship between menopause, whether surgical with or without oophorectomy, or natural, and coronary disease risk needs clarification. Dramatic changes during menopause in iron metabolism and hormone levels require prospective, granular studies to better understand and characterize the complex relationships occurring during this transition. One possibility is that iron in catalytic form stimulates inflammatory responses and leukocyte activity and associates with elevation of IL-6 and other inflammatory biomarkers based on our findings of direct associations (6) between elevated ferritin and inflammatory biomarkers, predominantly IL 6, and mortality.
Data from multiple sources support a need for additional studies testing the relationship between increased cardiovascular disease risk related to changing iron homeostasis, the role of inflammation and hormone status in women during and after surgical or natural menopause. Additionally, Gordon et al (2) reported unfavorable alterations in lipid metabolism with cessation of menses, most evident with bilateral oophorectomy plus hysterectomy. This risk factor may also play an important role. We recommend prospective serial measurements hormone replacement therapy (HRT) with estrogen and progestin or with estrogen alone, along with serial measures of hormone levels, lipid panels, ferritin, iron, hepcidin and inflammatory biomarkers in pre and postmenopausal women to better understand unique factors contributing to increased cardiovascular mortality. (4). An enhanced understanding of the biological basis for menopausal effects on cardiovascular disease offers important insights into prevention and treatment of cardiovascular disease generally.
Respectfully,
Virginia W Hayes, MS, APN, BC: VA Sierra Nevada Health Care System, Reno Nevada
Ralph G DePalma, MD: VA Office of Research and Development, Washington, DC. Department of Surgery, Uniformed University of the Health Sciences, Bethesda, Maryland.
Leo R Zacharski, MD; VA White River Junction Health Care System, White River, Vermont.
The authors are employees of the Department of Veterans Affairs and report no financial conflicts or interests. The opinions expressed are those of the authors and not necessarily those of the Veterans Administration or the Government of the United States.
1. Mytton J, Evison F, Lilford, LJ. 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
2. Gordon, T, Kannel WB, Hjortland, C, McNamara PM. Menopause and the risk of cardiovascular disease. The Framingham Study. Ann Intern Med 1978; 89 (2): 157-161
3. Muka T, Oliver-Williams C, Kunutsor S, et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: A systematic review and meta-analysis. JAMA Cardiol 2016; Sep 14: oi:10.1001/jamacardio.2016.2415
4. Hayes VW, DePalma RG, and Zacharski LR. Menstrual suppression, iron homeostasis, and disease risk. The Journal for Nurse Practitioners 2011; 7 (8): 660-664
5.. Zacharski LR, Shamayeva G, Chow, BK. Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial Disease. Am Heart J 2011; 162: 949-957.
6. DePalma RG, Hayes VW, Chow BK, Shamayeva G, May PE, Zacharski LR. Ferritin levels, inflammatory biomarkers, and mortality in peripheral arterial disease: A sub study of the Iron (Fe) and Atherosclerosis Study (FeAST) Trial. J Vasc Surg. 2010; 51(6): 1498–1503
Competing interests: No competing interests