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1.  Ovarian Cancer and Body Size: Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies 
PLoS Medicine  2012;9(4):e1001200.
A reanalysis of published and unpublished data from epidemiological studies examines the association between height, body mass index, and the risk of developing ovarian cancer.
Background
Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships.
Methods and Findings
Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index.
Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05–1.09; p<0.001); this relationship did not vary significantly by women's age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m2 increase in body mass index was 1.10 (95% CI, 1.07–1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92–0.99; p = 0.02) in ever-users of hormone therapy.
Conclusions
Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cancer of the ovaries, usually referred to as ovarian cancer, is the fifth leading cause of cancer death in women, and, unfortunately, symptoms (such as abdominal pain and swelling) usually occur late in the disease process; fewer than one-third of ovarian cancers are detected before they have spread outside of the ovaries. There is no definitive evidence that screening reduces mortality from ovarian cancer, and given the poor prognosis of advanced ovarian cancer, there has been much research over recent years to increase understanding of this serious condition. There are recognized risk factors that increase the chance of developing ovarian cancer, such as increasing age, having fewer children, not having used oral contraceptives, and use of menopausal hormone therapy. Age and oral contraceptive use have by far the biggest impact on ovarian cancer risk.
Why Was This Study Done?
To date, there is no definitive information about the relevance of women's height, weight, and body mass index to their subsequent risk of developing ovarian cancer. There have been roughly 50 epidemiological studies of ovarian cancer, but only about half of these studies have published results on the association between body size and ovarian cancer risk, and so far, these findings have been inconsistent. Therefore, the researchers—an international collaboration of researchers studying ovarian cancer—re-analyzed the available epidemiological evidence to investigate the relationship between ovarian cancer risk and adult height, weight, and body mass index, and to examine the consistency of the findings across study designs.
What Did the Researchers Do and Find?
After an extensive literature search, the researchers identified 47 eligible studies that collected individual data on women's reproductive history, use of hormonal therapies, height, weight, and/or body mass index, and in which the principal investigators of each study accepted the invitation from the researchers to be involved in the re-analysis. The researchers combined data from the different studies. To ensure that women in one study were only directly compared with controls (similar women without ovarian cancer) in the same study, all analyses were routinely stratified by study, center within study, age, parity, use of oral contraceptives, use of hormonal therapy for menopause, and menopausal status or hysterectomy.
The 47 studies were conducted in 14 countries and comprised a total of 25,157 women with ovarian cancer (mostly from Europe and North America) and 81,311 women without ovarian cancer. The researchers found a significant increase in relative risk (1.07) of ovarian cancer per 5 cm increase in height. Furthermore, this risk did not vary depending on other studied factors—age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. However, the researchers found that for body mass index, the risks depended on whether women had ever taken menopausal hormone therapy: the relative risk for ovarian cancer per 5 kg/m2 increase in body mass index was 1.10 in women who had never taken menopausal hormone therapy but was only 0.95 in women who had previously taken menopausal hormone therapy.
What Do These Findings Mean?
These findings suggest that increasing height can be considered as a risk factor for ovarian cancer and that in women who have never taken menopausal hormone therapy, increased body mass index can be considered an additional risk factor. These findings have public health implications, especially in high-income countries, because the average height of women has increased by about 1 cm per decade and average body mass index has increased by about 1 kg/m2 per decade. The findings suggest an associated increase in ovarian cancer incidence of 3% per decade if all other factors relevant for ovarian cancer remain constant.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001200.
The following organizations give more information on ovarian cancer which may be of use to patients: MedicineNet, the US National Cancer Institute, Ovarian Cancer National Alliance, Macmillan Cancer Support
doi:10.1371/journal.pmed.1001200
PMCID: PMC3317899  PMID: 22606070
2.  Long-term Mortality Associated with Oophorectomy versus Ovarian Conservation in the Nurses’ Health Study 
Obstetrics and gynecology  2013;121(4):709-716.
Objective
To report long-term mortality following oophorectomy or ovarian conservation at the time of hysterectomy in subgroups of women based on age at the time of surgery, use of estrogen therapy, presence of risk-factors for CHD and length of follow-up.
Methods
A prospective cohort study of 30,117 Nurses’ Health Study participants having a hysterectomy for benign disease Multivariable-adjusted hazard ratios [HR] for death from CHD, stroke, breast cancer, epithelial ovarian cancer, lung cancer, colorectal cancer, total cancer and all-causes were determined, comparing bilateral oophorectomy (n=16,914) with ovarian conservation (n=13,203).
Results
Over 28 years of follow-up, 16.8% of women with hysterectomy and bilateral oophorectomy died from all causes compared with 13.3% of women who had ovarian conservation (HR=1.13;95% confidence interval [CI] 1.06–1.21). Oophorectomy was associated with a lower risk of death from ovarian cancer (4v44) and prior to age 47.5 years a lower risk of death from breast cancer. However at no age was oophorectomy associated with a lower risk of other cause-specific or all-cause mortality. For women younger than 50 at the time of hysterectomy, bilateral oophorectomy was associated with significantly increased mortality in women who had never-used estrogen therapy, but not in past and current users: all-cause mortality (HR=1.41;95% CI, 1.04–1.92;Pinteraction=0.03); lung cancer mortality (HR=1.44;95% CI, 0.17–1.21;Pinteraction=0.02); and CHD mortality (HR=2.35;95% CI, 1.22–4.27;Pinteraction=0.02).
Conclusions
For women younger than 50 at the time of hysterectomy, bilateral oophorectomy was associated with significantly increased mortality in women who had never-used estrogen therapy. At no age was oophorectomy associated with increased overall survival.
doi:10.1097/AOG.0b013e3182864350
PMCID: PMC4254662  PMID: 23635669
3.  Thermal Balloon Endometrial Ablation for Dysfunctional Uterine Bleeding 
Executive Summary
Objectives
The objective of this review was to evaluate the effectiveness and cost-effectiveness of thermal balloon endometrial ablation (TBEA) for dysfunctional uterine bleeding (DUB).
Background: Condition and Target Population
Abnormal uterine bleeding is defined as an increase in the frequency of menstruation, duration of flow or amount of blood loss. (1) DUB is a diagnosis of exclusion when there is no pelvic pathology or underlying medical cause for the increased bleeding. (1) It is characterized by heavy prolonged flow with or without breakthrough bleeding. It may occur as frequent, irregular, or unpredictable bleeding; lengthy menstrual periods; bleeding between periods; or a heavy flow during periods. Menorrhagia, cyclical HMB over several consecutive cycles during the reproductive years, is the most frequent form of DUB.
The incidence of DUB has not been reported in the literature. For Ontario, an expert estimated that about 15% to 20% of women over 30 years have DUB. The prevalence increases with age and peaks just before menopause. (1) Using 2001 Ontario census-based population estimates, there are about 2 million women between the ages of 30 and 49 years; therefore, of these, about 290,965 to 387,953 may have DUB.
The Technology Being Reviewed: Thermal Balloon Endometrial Ablation
Since the 1990s, second-generation endometrial ablation (EA) techniques developed, the aim to provide simpler, quicker, and more effective treatment options for menorrhagia compared with first-generation EA techniques and hysterectomy. (2) Compared with first-generation techniques these depend less on the people operating them and more on the actual devices to ensure safety and efficacy.
TBEA relies on the transfer of heat from heated liquid within a balloon that is inserted into the uterus. (2) It does not require a hysteroscope for direct visualization of the uterus and can be performed under local anesthesia. In order to use TBEA, patients with DUB cannot have a long (>10–12 cm) or irregularly shaped uterine cavity, because the balloon must be in direct contact with the uterine wall to cause ablation. For Ontario, an expert estimated that about 70% of patients with DUB considered for EA would have a uterus suitable for TBEA based on these criteria. If 70% of Ontario women between 30 and 49 years of age with DUB have a uterus suitable for TBEA, then about 203,675 to 271,567 women may be eligible. However, some of these women will be successfully treated by drugs or will want amenorrhea (the cessation of their periods) and therefore choose to have a hysterectomy.
Review Strategy
The standard Medical Advisory Secretariat search strategy was used to locate international health technology assessments and English-language journal articles published from January 1996 to June 2004. A Cochrane systematic review from 2004 was identified that examined the effectiveness and cost-effectiveness of TBEA for heavy menstrual bleeding. (2) Another literature search was done to update information from the systematic review.
Summary of Findings
A 2004 systematic review of the literature by Garside et al. (2) in the United Kingdom, found that overall, there were few significant differences between outcomes for first-generation techniques and TBEA. The outcomes were bleeding, postoperative complications, patient satisfaction, quality of life, and repeat surgery rates. Significant differences were reported most often by one study by Pellicano et al., (3) but this was a level 2 study with methodological weaknesses. Furthermore, according to Garside et al., there was considerable clinical and methodological heterogeneity among the studies in the systematic review. Therefore, a quantitative synthesis using meta-analysis was not done. In Garfield and colleagues’ review:
TBEA had significantly shorter operating and theatre times (P < .05, < .01, and .0001).
TBEA had fewer intraoperative adverse effects (e.g., reported rates of uterine perforation with RB ablation: from 1% to 5%; TBEA: 0%; rates of cervical laceration with RB: 2% to 5%; TBEA 0%).
They found no studies have directly compared second-generation techniques and hysterectomy; therefore, the comparison can only be indirectly inferred from studies of first-generation techniques and hysterectomy.
Compared with hysterectomy, TCRE and RB are quicker to perform and result in shorter hospitalization stays and a faster return to work.
Hysterectomy results in more adverse effects.
Satisfaction with hysterectomy is initially higher, but there is no difference after 2 years.
Studies (level 2 evidence) published after Garside’s systematic review support these conclusions.
A study with level 2 evidence reported a significantly higher risk overall of intraoperative complications for RB compared with TBEA (P < .001). This included uterine perforation (RB, 5%; TBEA, 0%) and suspicion of perforation (RB, 2%; TBEA, 0%).
A multicentre long-term case series (level 4 evidence) that examined avoidance of hysterectomy after TBEA for menorrhagia reported that 86% of women who had TBEA did not require a hysterectomy, and 75% did not have any further surgery during a follow-up period of 4 to 6 years. (4)
Several TBEA studies did not provide justification for using general anesthesia over local anesthesia.
Patient preferences for different treatments will depend on a woman’s desire for amenorrhea as an outcome and/or avoidance of major surgery. Hysterectomy is the only procedure that can guarantee amenorrhea. TBEA will not totally replace hysterectomy in the treatment of DUB, because some women may want cessation of menstruation.
Ensuring that patient expectations are consistent with the outcomes achievable with TBEA is important to obtain high levels of satisfaction. Vilos et al. (5) noted that up to one-half of patients who underwent a second attempt at TBEA might have avoided the second procedure with proper preoperative counselling. Meyer et al. (6) noted that one consideration for patients with menorrhagia (and no structural lesions) is to return to normal or less blood loss rather than amenorrhea. Patients may have distinct concepts of menstrual bleeding depending on cultural background, and maintaining an acceptable menstrual flow instead of amenorrhea may represent a healthier status. (7)
A budget impact analysis suggests that the net annual budget outlay for TBEA would be between $1.4 million in savings and $2.8 million in additional outlays. (Note: Not all savings would be realized directly by the Ministry of Health and Long-Term Care, because much of the savings would accrue to the global budgets of hospitals).
Conclusions
TBEA is effective, safe, and cost-effective for patients with DUB.
For women who are not worried about amenorrhea, first-generation techniques offer advantages over hysterectomy.
TBEA is a better alternative to first-generation techniques for DUB, because it is associated with fewer intraoperative adverse effects.
PMCID: PMC3387747  PMID: 23074450
4.  Ovarian Conservation at the Time of Hysterectomy and Long-Term Health Outcomes in the Nurses’ Health Study 
Obstetrics and gynecology  2009;113(5):1027-1037.
Objective
To report long-term health outcomes and mortality after oophorectomy or ovarian conservation.
Methods
We conducted a prospective, observational study of 29,380 women participants of the Nurses’ Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes.
Results
Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy, compared with ovarian conservation, the multivariable hazard ratios (HR) were 1.12 (95% CI 1.03, 1.21) for total mortality, 1.17 (95% CI 1.02, 1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98, 1.33) for stroke. Although the risks of breast (HR 0.75 95% CI 0.68, 0.84), ovarian (HR 0.04 95% CI 0.01, 0.09, NNT = 220), and total cancers (HR 0.92 95% CI 0.86, 0.98) decreased after oophorectomy, lung cancer incidence (HR =1.26, 95% CI 1.02, 1.56, NNH = 190) and total cancer mortality (HR=1.17, 95% CI 1.04, 1.32) increased. For never-users of estrogen therapy, bilateral oophorectomy before age 50 was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span following surgery, one additional death would be expected for every 9 oophorectomies performed.
Conclusions
Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer, but an increased risk of all-cause mortality, fatal and non-fatal coronary heart disease, and lung cancer. In no analysis or age-group was oophorectomy associated with increased survival.
doi:10.1097/AOG.0b013e3181a11c64
PMCID: PMC3791619  PMID: 19384117
5.  Fibroids (uterine myomatosis, leiomyomas) 
Clinical Evidence  2011;2011:0814.
Introduction
Between 5% and 77% of women may have fibroids, depending on the method of diagnosis used. Fibroids may be asymptomatic, or may present with menorrhagia, pain, infertility, or recurrent pregnancy loss. Risk factors for fibroids include obesity, having no children, and no long-term use of the oral contraceptive pill. Fibroids tend to shrink or fibrose after the menopause.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: medical treatment alone; preoperative medical treatments for women scheduled for surgery; and surgical treatments in women with fibroids? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 54 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: gonadorelin analogues (with progestogen, raloxifene, tibolone, or combined oestrogen–progestogen), hysterectomy (plus oophorectomy), hysteroscopic resonance-focused ultrasound, laparoscopic myomectomy, laparoscopically assisted vaginal hysterectomy, rollerball endometrial ablation, thermal balloon ablation, thermal myolysis with laser, total abdominal hysterectomy, total abdominal myomectomy, total laparoscopic hysterectomy, total vaginal hysterectomy, and uterine artery embolisation.
Key Points
Between 5% and 77% of women may have fibroids, depending on the method of diagnosis used. Fibroids may be asymptomatic, or may present with menorrhagia, pain, infertility, or recurrent pregnancy loss. Risk factors for fibroids include obesity, having no children, and no long-term use of the oral contraceptive pill. Fibroids tend to shrink or fibrose after the menopause.
Gonadorelin analogues reduce bleeding compared with placebo, but can cause menopausal symptoms and bone loss, which may limit their long-term use. Adding progesterone, tibolone, or raloxifene to gonadorelin analogues may prevent these adverse effects, but their addition doesn't produce any greater effect on fibroid symptoms than gonadorelin analogues alone.
We don't know whether NSAIDs or the levonorgestrel intrauterine system improve symptoms of fibroids.
Gonadorelin analogues given before fibroid surgery reduce bleeding, and increase the likelihood of having a vaginal rather than abdominal hysterectomy, but increase anti-oestrogenic adverse effects (such as hot flushes, change in breast size, vaginal symptoms).
Total abdominal hysterectomy is considered to be beneficial in reducing fibroid-related symptoms, but total vaginal hysterectomy and total laparoscopic hysterectomy may have lower risks of complications, and shorter recovery times. Laparoscopically assisted vaginal hysterectomy may increase operative times and blood loss compared with total vaginal hysterectomy.
Myomectomy maintains fertility, but we don't know whether it is better at reducing fibroid symptoms compared with hysterectomy. Laparoscopic myomectomy reduces complications and recovery time compared with abdominal myomectomy.
We don't know whether thermal myolysis with laser, hysteroscopic resection, thermal balloon ablation, rollerball endometrial ablation, or magnetic resonance-guided focused ultrasound surgery are beneficial in women with fibroids compared with hysterectomy, as we found no studies.
Uterine artery embolisation reduces duration of surgery, hospital stay, postoperative pain, and recovery time compared with surgery (hysterectomy or myomectomy) and reduces blood loss compared with hysterectomy. Symptom scores and reproductive outcomes may be poorer with uterine artery embolisation compared with surgery or myomectomy respectively, and a proportion of women undergoing uterine artery embolisation may require future surgery for treatment failure.
PMCID: PMC3217738  PMID: 21477393
6.  Cervical cancer 
Clinical Evidence  2011;2011:0818.
Introduction
Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme, to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33. Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5–15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent cervical cancer? What are the effects of interventions to manage early-stage cervical cancer? What are the effects of interventions to manage bulky early-stage cervical cancer? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: human papillomavirus (HPV) vaccine for preventing cervical cancer; conisation of the cervix for microinvasive carcinoma (stage Ia1), conisation of the cervix plus lymphadenectomy (stage Ia2 and low-volume, good prognostic factor stage Ib), radical trachelectomy for low-volume stage Ib disease, neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or different types of hysterectomy versus each other for treating early-stage and bulky early-stage cervical cancer.
Key Points
Worldwide, cervical cancer is the third most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme to the current level of approximately 2334 women in 2008, with a mortality to incidence ratio of 0.33.About 80% of tumours are squamous type, and staging is based on the FIGO classification.Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5–15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.Development of cervical cancer is strongly associated with HPV infection, acquired mainly by sexual intercourse.The peak prevalence of HPV infection is 20–40% in women aged 20 to 30 years, but in 80% of cases the infection resolves within 12 to 18 months.Other risk factors for cervical cancer include early onset of sexual activity, multiple sexual partners, long-term use of oral contraceptives, tobacco smoking, low socioeconomic status, and immunosuppressive therapy.
Vaccination against HPV is effective in preventing certain types of oncogenic HPV infection, and at reducing rates of cervical intraepithelial neoplasia, but there has been insufficient long-term follow-up to assess effects on cervical cancer rates.
Conisation with adequate excision margins is considered effective for microinvasive carcinoma (stage Ia1), and can preserve fertility, unlike simple hysterectomy; however, it has been associated with an increased risk of preterm delivery and low birth weight. Conisation is often performed for stage Ia1 disease, but evidence for its benefit is from observational studies only.
We don’t know how conisation of the cervix with pelvic lymphadenectomy and simple or radical hysterectomy compare with each other for stage Ia2 and low volume stage 1b cervical cancer, as we found no RCTs.
We don’t know how simple hysterectomy plus lymphadenectomy and radical hysterectomy plus lymphadenectomy compare with each other, in early cervical cancer, as we found no RCT evidence.
Limited observational evidence shows that radical trachelectomy plus lymphadenectomy results in similar disease-free survival as radical hysterectomy in women with early-stage cervical cancer; however, we found no RCTs. Radical trachelectomy plus lymphadenectomy can preserve fertility.
Limited RCT evidence shows that radiotherapy is as effective as surgery in early-stage disease. Overall and disease-free survival are similar after radiotherapy or radical hysterectomy plus lymphadenectomy, but radiotherapy is less likely to cause severe adverse effects.
Chemoradiotherapy improves survival compared with radiotherapy in women with bulky early-stage cervical cancer. Combined chemoradiotherapy improves overall and progression-free survival when used either before or after hysterectomy, but is associated with more haematological and gastrointestinal toxicity compared with radiotherapy alone.
The benefits of neoadjuvant chemotherapy plus surgery compared with radiotherapy alone are unknown.
PMCID: PMC3217784  PMID: 21791123
7.  Fibroids (uterine myomatosis, leiomyomas) 
Clinical Evidence  2007;2007:0814.
Introduction
Between 5-77% of women may have fibroids, depending on the method of diagnosis used. Fibroids may be asymptomatic, or may present with menorrhagia, pain, infertility, or recurrent pregnancy loss. Risk factors for fibroids include obesity, having no children, and no long-term use of the oral contraceptive pill. Fibroids tend to shrink or fibrose after the menopause.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: medical treatment alone; preoperative medical treatments for women scheduled for surgery; and surgical treatments in women with fibroids? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: gonadorelin analogues (with progestogen, raloxifene, tibolone, or combined oestrogen-progestogen); hysterectomy (plus oophorectomy); hysteroscopic resonance-focused ultrasound; laparoscopic myomectomy; laparoscopically assisted vaginal hysterectomy; rollerball endometrial ablation; thermal balloon ablation; thermal myolysis with laser; total abdominal hysterectomy; total abdominal myomectomy; total laparoscopic hysterectomy; total vaginal hysterectomy.
Key Points
Between 5-77% of women may have fibroids, depending on the method of diagnosis used. Fibroids may be asymptomatic, or may present with menorrhagia, pain, infertility, or recurrent pregnancy loss. Risk factors for fibroids include obesity, having no children, and no long-term use of the oral contraceptive pill. Fibroids tend to shrink or fibrose after the menopause.
Gonadorelin analogues reduce bleeding compared with placebo, but can cause menopausal symptoms and bone loss, which may limit their long-term use. Adding progesterone, tibolone, or raloxifene to gonadorelin analogues may prevent these adverse effects, but their addition doesn't produce any greater effect on fibroid symptoms than gonadorelin analogues alone.
We don't know whether NSAIDs or the levonorgestrel intrauterine system improve symptoms of fibroids.
Gonadorelin analogues given before fibroid surgery reduce bleeding, and increase the likelihood of having a vaginal rather than abdominal hysterectomy, but increase anti-oestrogenic adverse effects (such as hot flushes, change in breast size, vaginal symptoms).
Total abdominal hysterectomy is considered to be beneficial in reducing fibroid-related symptoms, but total vaginal hysterectomy and total laparoscopic hysterectomy may have lower risks of complications, and shorter recovery times. Laparoscopically assisted vaginal hysterectomy may increase operative times and blood loss compared with total vaginal hysterectomy.
Myomectomy maintains fertility, but we don't know whether it is better at reducing fibroid symptoms compared with hysterectomy. Laparoscopic myomectomy reduces complications and recovery time compared with abdominal myomectomy.We don't know whether thermal myolysis with laser, hysteroscopic resection, thermal balloon ablation, or rollerball ablation, or magnetic resonance-guided focused ultrasound surgery are beneficial in women with fibroids compared with hysterectomy, as we found no studies.
PMCID: PMC2943812  PMID: 19454074
8.  Smoking and high-risk mammographic parenchymal patterns: a case-control study 
Breast Cancer Research  1999;2(1):59-63.
Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern. Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to the mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results are still strongly suggestive. The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate that smoking is a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It appears that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
Introduction:
Overall, epidemiological studies [1,2,3,4] have reported no substantial association between cigarette smoking and the risk of breast cancer. Some studies [5,6,7] reported a significant increase of breast cancer risk among smokers. In recent studies that addressed the association between breast cancer and cigarette smoking, however, there was some suggestion of a decreased risk [8,9,10], especially among current smokers, ranging from approximately 10 to 30% [9,10]. Brunet et al [11] reported that smoking might reduce the risk of breast cancer by 44% in carriers of BRCA1 or BRCA2 gene mutations. Wolfe [12] described four different mammographic patterns created by variations in the relative amounts of fat, epithelial and connective tissue in the breast, designated N1, P1, P2 and DY. Women with either P2 or DY pattern are considered at greater risk for breast cancer than those with N1 or P1 pattern [12,13,14,15]. There are no published studies that assessed the relationship between smoking and mammographic parenchymal patterns.
Aims:
To evaluate whether mammographic parenchymal patterns as classified by Wolfe, which have been positively associated with breast cancer risk, are affected by smoking. In this case-control study, nested within the European Prospective Investigation on Cancer in Norfolk (EPIC-Norfolk) cohort [16], the association between smoking habits and mammographic parenchymal patterns are examined. The full results will be published elsewhere.
Methods:
Study subjects were members of the EPIC cohort in Norwich who also attended the prevalence screening round at the Norwich Breast Screening Centre between November 1989 and December 1997, and were free of breast cancer at that screening. Cases were defined as women with a P2/DY Wolfe's mammographic parenchymal pattern on the prevalence screen mammograms. A total of 203 women with P2/DY patterns were identified as cases and were individually matched by date of birth (within 1 year) and date of prevalence screening (within 3 months) with 203 women with N1/P1 patterns who served as control individuals.
Two views, the mediolateral and craniocaudal mammograms, of both breasts were independently reviewed by two of the authors (ES and RW) to determine the Wolfe mammographic parenchymal pattern.
Considerable information on health and lifestyle factors was available from the EPIC Health and Lifestyle Questionnaire [16]. In the present study we examined the subjects' personal history of benign breast diseases, menstrual and reproductive factors, oral contraception and hormone replacement therapy, smoking, and anthropometric information such as body mass index and waist:hip ratio.
Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by conditional logistic regression [17], and were adjusted for possible confounding factors.
Results:
The characteristics of the cases and controls are presented in Table 1. Cases were leaner than controls. A larger percentage of cases were nulliparous, premenopausal, current hormone replacement therapy users, had a personal history of benign breast diseases, and had had a hysterectomy. A larger proportion of controls had more than three births and were current smokers.
Table 2 shows the unadjusted and adjusted OR estimates for Wolfe's high-risk mammographic parenchymal patterns and smoking in the total study population and in postmenopausal women separately. Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern (OR 0.37, 95% CI 0.14-0.94). Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results were still strongly suggestive. There was no interaction between cigarette smoking and body mass index.
Discussion:
In the present study we found a strong inverse relationship between current smoking and high-risk mammographic parenchymal patterns of breast tissue as classified by Wolfe [12]. These findings are not completely unprecedented; Greendale et al [18] found a reduced risk of breast density in association with smoking, although the magnitude of the reduction was unclear. The present findings suggest that this reduction is large.
Recent studies [9,10] have suggested that breast cancer risk may be reduced among current smokers. In a multicentre Italian case-control study, Braga et al [10] found that, relative to nonsmokers, current smokers had a reduced risk of breast cancer (OR 0.84, 95% CI 0.7-1.0). These findings were recently supported by Gammon et al [9], who reported that breast cancer risk in younger women (younger than 45 years) may be reduced among current smokers who began smoking at an early age (OR 0.59, 95% CI 0.41-0.85 for age 15 years or younger) and among long-term smokers (OR 0.70, 95% CI 0.52-0.94 for those who had smoked for 21 years or more).
The possible protective effect of smoking might be due to its anti-oestrogenic effect [1,2,19]. Recently there has been renewed interest in the potential effect of smoking on breast cancer risk, and whether individuals may respond differently on the basis of differences in metabolism of bioproducts of smoking [20,21]. Different relationships between smoking and breast cancer risk have been suggested that are dependent on the rapid or slow status of acetylators of aromatic amines [20,21]. More recent studies [22,23], however, do not support these findings.
The present study design minimized the opportunity for bias to influence the findings. Because subjects were unaware of their own case-control status, the possibility of recall bias in reporting smoking status was minimized. Systematic error in the assessment of mammograms was avoided because reading was done without knowledge of the risk factor data. Furthermore, the associations observed are unlikely to be explained by the confounding effect of other known breast cancer risk factors, because we adjusted for these in the analysis. We did not have information on passive smoking status, however, which has recently been reported to be a possible confounder [5,6,21,24].
The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate smoking as a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It seems that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.
PMCID: PMC13911  PMID: 11056684
mammography; screening; smoking; Wolfe's parenchymal patterns
9.  Robotic-Assisted Minimally Invasive Surgery for Gynecologic and Urologic Oncology 
Executive Summary
Objective
An application was received to review the evidence on the ‘The Da Vinci Surgical System’ for the treatment of gynecologic malignancies (e.g. endometrial and cervical cancers). Limitations to the current standard of care include the lack of trained physicians on minimally invasive surgery and limited access to minimally invasive surgery for patients. The potential benefits of ‘The Da Vinci Surgical System’ include improved technical manipulation and physician uptake leading to increased surgeries, and treatment and management of these cancers.
The demand for robotic surgery for the treatment and management of prostate cancer has been increasing due to its alleged benefits of recovery of erectile function and urinary continence, two important factors of men’s health. The potential technical benefits of robotic surgery leading to improved patient functional outcomes are surgical precision and vision.
Clinical Need
Uterine and cervical cancers represent 5.4% (4,400 of 81,700) and 1.6% (1,300 of 81,700), respectively, of incident cases of cancer among female cancers in Canada. Uterine cancer, otherwise referred to as endometrial cancer is cancer of the lining of the uterus. The most common treatment option for endometrial cancer is removing the cancer through surgery. A surgical option is the removal of the uterus and cervix through a small incision in the abdomen using a laparoscope which is referred to as total laparoscopic hysterectomy. Risk factors that increase the risk of endometrial cancer include taking estrogen replacement therapy after menopause, being obese, early age at menarche, late age at menopause, being nulliparous, having had high-dose radiation to the pelvis, and use of tamoxifen.
Cervical cancer occurs at the lower narrow end of the uterus. There are more treatment options for cervical cancer compared to endometrial cancer, however total laparoscopic hysterectomy is also a treatment option. Risk factors that increase the risk for cervical cancer are multiple sexual partners, early sexual activity, infection with the human papillomavirus, and cigarette smoking, whereas barrier-type of contraception as a risk factor decreases the risk of cervical cancer.
Prostate cancer is ranked first in men in Canada in terms of the number of new cases among all male cancers (25,500 of 89,300 or 28.6%). The impact on men who develop prostate cancer is substantial given the potential for erectile dysfunction and urinary incontinence. Prostate cancer arises within the prostate gland, which resides in the male reproductive system and near the bladder. Radical retropubic prostatectomy is the gold standard treatment for localized prostate cancer. Prostate cancer affects men above 60 years of age. Other risk factors include a family history of prostate cancer, being of African descent, being obese, consuming a diet high in fat, physical inactivity, and working with cadium.
The Da Vinci Surgical System
The Da Vinci Surgical System is a robotic device. There are four main components to the system: 1) the surgeon’s console, where the surgeon sits and views a magnified three-dimensional image of the surgical field; 2) patient side-cart, which sits beside the patient and consists of three instrument arms and one endoscope arm; 3) detachable instruments (endowrist instruments and intuitive masters), which simulate fine motor human movements. The hand movements of the surgeon’s hands at the surgeon’s console are translated into smaller ones by the robotic device and are acted out by the attached instruments; 4) three-dimensional vision system: the camera unit or endoscope arm. The main advantages of use of the robotic device are: 1) the precision of the instrument and improved dexterity due to the use of “wristed” instruments; 2) three-dimensional imaging, with improved ability to locate blood vessels, nerves and tissues; 3) the surgeon’s console, which reduces fatigue accompanied with conventional laparoscopy surgery and allows for tremor-free manipulation. The main disadvantages of use of the robotic device are the costs including instrument costs ($2.6 million in US dollars), cost per use ($200 per use), the costs associated with training surgeons and operating room personnel, and the lack of tactile feedback, with the trade-off being increased visual feedback.
Research Questions
For endometrial and cervical cancers,
1. What is the effectiveness of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
2. What are the incremental costs of the Da Vinci Surgical System vs. laparoscopy and laparotomy for women undergoing any hysterectomy for the surgical treatment and management of their endometrial and cervical cancers?
For prostate cancer,
3. What is the effectiveness of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
4. What are the incremental costs of robotically-assisted radical prostatectomy using the Da Vinci Surgical System vs. laparoscopic radical prostatectomy and retropubic radical prostatectomy for the surgical treatment and management of prostate cancer?
Research Methods
Literature Search
Search Strategy
A literature search was performed on May 12, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, CINAHL, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment for studies published from January 1, 2000 until May 12, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language articles (January 1, 2000-May 12, 2010)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a primary data source (e.g. obtained in a clinical setting)
Journal articles that report on the effectiveness or cost-effectiveness for the comparisons of interest using a secondary data source (e.g. hospital- or population-based registries)
Study design and methods must be clearly described
Health technology assessments, systematic reviews, randomized controlled trials, non-randomized controlled trials and/or cohort studies, case-case studies, regardless of sample size, cost-effectiveness studies
Exclusion Criteria
Duplicate publications (with the more recent publication on the same study population included)
Non-English papers
Animal or in-vitro studies
Case reports or case series without a referent or comparison group
Studies on long-term survival which may be affected by treatment
Studies that do not examine the cancers (e.g. advanced disease) or outcomes of interest
Outcomes of Interest
For endometrial and cervical cancers,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Number of complications*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of conversions to laparotomy*
Number of lymph nodes recovered
For prostate cancer,
Primary outcomes:
Morbidity factors
- Length of hospitalization
- Amount of morphine use/pain*
Peri-operative factors
- Operation time
- Amount of blood loss*
- Number of transfusions*
- Duration of catheterization
- Number of complications*
- Number of anastomotic strictures*
Number of lymph nodes recovered
Oncologic factors
- Proportion of positive surgical margins
Long-term outcomes
- Urinary continence
- Erectile function
Summary of Findings
Robotic use for gynecologic oncology compared to:
Laparotomy: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations.
The beneficial effect of robotic surgery was shown in pooled analysis for complications, owing to increased sample size.
More work is needed to clarify the role of complications in terms of safety, including improved study designs, analysis and measurement.
Laparoscopy: benefits of robotic surgery in terms of shorter length of hospitalization, less blood loss and fewer conversions to laparotomy likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for length of hospitalizations and blood loss is low.
Fewer conversions to laparotomy indicate clinical effectiveness in terms of reduced morbidity.
Robotic use for urologic oncology, specifically prostate cancer, compared to:
Retropubic surgery: benefits of robotic surgery in terms of shorter length of hospitalization and less blood loss/fewer individuals requiring transfusions. These results indicate clinical effectiveness in terms of reduced morbidity and safety, respectively, in the context of study design limitations. There was a beneficial effect in terms of decreased positive surgical margins and erectile dysfunction. These results indicate clinical effectiveness in terms of improved cancer control and functional outcomes, respectively, in the context of study design limitations.
Surgeon skill had an impact on cancer control and functional outcomes.
The results for complications were inconsistent when measured as either total number of complications, pain management or anastomosis. There is some suggestion that robotic surgery is safe with respect to less post-operative pain management required compared to retropubic surgery, however improved study design and measurement of complications need to be further addressed.
Clinical significance of significant findings for length of hospitalizations is low.
Laparoscopy: benefits of robotic surgery in terms of less blood loss and fewer individuals requiring transfusions likely owing to the technical difficulty of conventional laparoscopy, in the context of study design limitations.
Clinical significance of significant findings for blood loss is low.
The potential link between less blood loss, improved visualization and improved functional outcomes is an important consideration for use of robotics.
All studies included were observational in nature and therefore the results must be interpreted cautiously.
Economic Analysis
The objective of this project was to assess the economic impact of robotic-assisted laparoscopy (RAL) for endometrial, cervical, and prostate cancers in the province of Ontario.
A budget impact analysis was undertaken to report direct costs associated with open surgery (OS), endoscopic laparoscopy (EL) and robotic-assisted laparoscopy (RAL) based on clinical literature review outcomes, to report a budget impact in the province based on volumes and costs from administrative data sets, and to project a future impact of RAL in Ontario. A cost-effectiveness analysis was not conducted because of the low quality evidence from the clinical literature review.
Hospital costs were obtained from the Ontario Case Costing Initiative (OCCI) for the appropriate Canadian Classification of Health Intervention (CCI) codes restricted to selective ICD-10 diagnostic codes after consultation with experts in the field. Physician fees were obtained from the Ontario Schedule of Benefits (OSB) after consultation with experts in the field. Fees were costed based on operation times reported in the clinical literature for the procedures being investigated. Volumes of procedures were obtained from the Ministry of Health and Long-Term Care (MOHLTC) administrative databases.
Direct costs associated with RAL, EL and OS included professional fees, hospital costs (including disposable instruments), radiotherapy costs associated with positive surgical margins in prostate cancer and conversion to OS in gynecological cancer. The total cost per case was higher for RAL than EL and OS for both gynecological and prostate cancers. There is also an acquisition cost associated with RAL. After conversation with the only supplier in Canada, hospitals are looking to spend an initial 3.6M to acquire the robotic surgical system
Previous volumes of OS and EL procedures were used to project volumes into Years 1-3 using a linear mathematical expression. Burden of OS and EL hysterectomies and prostatectomies was calculated by multiplying the number of cases for that year by the cost/case of the procedure.
The number of procedures is expected to increase in the next three years based on historical data. RAL is expected to capture this market by 65% after consultation with experts. If it’s assumed that RAL will capture the current market in Ontario by 65%, the net impact is expected to be by Year 3, 3.1M for hysterectomy and 6.7M for prostatectomy procedures respectively in the province.
RAL has diffused in the province with four surgical systems in place in Ontario, two in Toronto and two in London. RAL is a more expensive technology on a per case basis due to more expensive robot specific instrumentation and physician labour reflected by increased OR time reported in the clinical literature. There is also an upfront cost to acquire the machine and maintenance contract. RAL is expected to capture the market at 65% with project net impacts by Year 3 of 3.1M and 6.7M for hysterectomy and prostatectomy respectively.
PMCID: PMC3382308  PMID: 23074405
10.  Comparative Effectiveness of Robotic Versus Laparoscopic Hysterectomy for Endometrial Cancer 
Journal of Clinical Oncology  2012;30(8):783-791.
Purpose
Use of robotics in oncologic surgery is increasing; however, reports of safety and efficacy are from highly experienced surgeons and centers. We performed a population-based analysis to compare laparoscopic hysterectomy and robotic hysterectomy for endometrial cancer.
Patients and Methods
The Perspective database was used to identify women who underwent a minimally invasive hysterectomy for endometrial cancer from 2008 to 2010. Morbidity, mortality, and cost were evaluated using multivariable logistic and linear regression models.
Results
We identified 2,464 women, including 1,027 (41.7%) who underwent laparoscopic hysterectomy and 1,437 (58.3%) who underwent robotic hysterectomy. Women treated at larger hospitals, nonteaching hospitals, and centers outside of the northeast were more likely to undergo a robotic hysterectomy procedure, whereas black women, those without insurance, and women in rural areas were less likely to undergo a robotic hysterectomy procedure (P < .05 for all). The overall complication rate was 9.8% for laparoscopic hysterectomy versus 8.1% for robotic hysterectomy (P = .13). The adjusted odds ratio (OR) for any morbidity for robotic hysterectomy was 0.76 (95% CI, 0.56 to 1.03). After adjusting for patient, surgeon, and hospital characteristics, there were no significant differences in the rates of intraoperative complications (OR, 0.68; 95% CI, 0.42 to 1.08), surgical site complications (OR, 1.49; 95% CI, 0.81 to 2.73), medical complications (OR, 0.64; 95% CI, 0.40 to 1.01), or prolonged hospitalization (OR, 0.85; 95% CI, 0.64 to 1.14) between the procedures. The mean cost for robotic hysterectomy was $10,618 versus $8,996 for laparoscopic hysterectomy (P < .001). In a multivariable model, robotic hysterectomy was significantly more costly ($1,291; 95% CI, $985 to $1,597).
Conclusion
Despite claims of decreased complications with robotic hysterectomy, we found similar morbidity but increased cost compared with laparoscopic hysterectomy. Comparative long-term efficacy data are needed to justify its widespread use.
doi:10.1200/JCO.2011.36.7508
PMCID: PMC3295567  PMID: 22291073
11.  Pre-diagnosis oophorectomy, estrogen therapy and mortality in a cohort of women diagnosed with breast cancer 
Introduction
Pre-diagnosis oophorectomy and estrogen therapy could impact mortality due to breast cancer and cardiovascular disease (CVD) among breast cancer survivors. Elective bilateral oophorectomy at the time of hysterectomy for benign conditions is not uncommon among US women.
Methods
We examined the association between pre-diagnosis total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO) and both overall and cause-specific mortality in the Collaborative Breast Cancer Studies cohort. Medical history and prior estrogen use were collected during standardized telephone interviews. Vital status, including date and cause of death, was obtained by linkage with the National Death Index. Multivariate hazard ratios (HR) and 95% confidence intervals (CI) for cause-specific mortality were calculated using Cox proportional hazards regression.
Results
Seventeen percent (N = 1,778) of breast cancer survivors (mean age at diagnosis = 63.5) reported pre-diagnosis TAHBSO. During follow-up (mean = 9.5 years), 2,856 deaths occurred, including 1,060 breast cancer deaths and 459 CVD deaths. Breast cancer deaths occurred a median of 5.1 years after diagnosis; CVD deaths occurred further from diagnosis (median = 9.7 years). Women who reported pre-diagnosis TAHBSO had a 16% decrease in all-cause mortality (HR = 0.84; 95% CI: 0.76, 0.92) compared to those with an intact uterus and ovaries. This overall decrease reflected a 27% lower breast cancer mortality among women who never used postmenopausal hormones (HR = 0.73; CI: 0.55, 0.96) and 43% lower CVD risk among women who reported using estrogen (HR = 0.57; CI: 0.39, 0.83) after TAHBSO.
Conclusions
Information on prior TAHBSO and estrogen use can inform risk of death from both breast cancer and cardiovascular disease among breast cancer survivors.
doi:10.1186/bcr3560
PMCID: PMC3978665  PMID: 24152546
12.  Factors Associated With Peripartum Hysterectomy 
Obstetrics and gynecology  2009;114(1):115-123.
Objective
To identify factors associated with peripartum hysterectomy performed within 30 days postpartum.
Methods
This was a population-based case-control study using Washington State birth certificate registry (1987-2006) linked to the Comprehensive Hospital Abstract Reporting System (CHARS). Cases underwent hysterectomy within 30 days postpartum. Controls were frequency matched 4:1. Exposures included factors related to hemorrhage, delivery method, multiple gestations, and infection. Incidence rates of peripartum hysterectomy and maternal and neonatal morbidity/mortality were assessed. Adjusted odds ratios (aOR) by maternal age, parity, gestational age, year of birth, and mode of delivery and 95% confidence intervals (CI) were computed.
Results
There were 896 hysterectomies. Incidence rates ranged from 0.25 in 1987to 0.82 per 1,000 deliveries in 2006 (χ2 for trend, p<0.001). Factors related to hemorrhage were strongly related to peripartum hysterectomy. Placenta previa (192 cases vs. 23 controls; aOR=7.9, 95% CI: 4.1– 15.0), abruptio placenta (71 vs. 55; aOR=3.2, 95% CI: 1.8–5.8), and retained placenta (214 vs. 28; aOR=43.0, 95% CI: 19.0–97.7) increased the risk of hysterectomy, as did uterine atony, uterine rupture, and thrombocytopenia. Having multiple gestations did not. As compared with vaginal delivery, vaginal delivery after cesarean (27 cases vs. 105 controls; aOR=1.9, 95% CI: 1.2–3.0), primary cesarean (270 vs. 504; aOR=4.6, 95% CI: 3.5–6.0), and repeat cesarean (296 vs. 231; aOR=7.9, 95% CI: 5.8-10.7) increased the risk of peripartum hysterectomy. Among the 111 women who had hysterectomy on readmission (12.8% of cases), hemorrhage- and infection-related factors were still strongly associated with peripartum hysterectomy.
Conclusion
Incidence rates of peripartum hysterectomy are increasing over time. The most important risk factor for peripartum hysterectomy is hemorrhage, most notably caused by uterine rupture, retained placenta, and atony of uterus.
doi:10.1097/AOG.0b013e3181a81cdd
PMCID: PMC2714706  PMID: 19546767
13.  Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from Royal College of General Practitioners’ oral contraception study 
BMJ : British Medical Journal  1999;318(7176):96-100.
Objective
To describe the long term effects of the use of oral contraceptives on mortality.
Design
Cohort study with 25 year follow up. Details of oral contraceptive use and of morbidity and mortality were reported six monthly by general practitioners. 75% of the original cohort was “flagged” on the NHS central registers.
Setting
1400 general practices throughout Britain.
Subjects
46 000 women, half of whom were using oral contraceptives at recruitment in 1968-9. Median age at end of follow up was 49 years.
Main outcome measures
Relative risks of death adjusted for age, parity, social class, and smoking.
Results
Over the 25 year follow up 1599 deaths were reported. Over the entire period of follow up the risk of death from all causes was similar in ever users and never users of oral contraceptives (relative risk=1.0, 95% confidence interval 0.9 to 1.1; P=0.7) and the risk of death for most specific causes did not differ significantly in the two groups. However, among current and recent (within 10 years) users the relative risk of death from ovarian cancer was 0.2 (0.1 to 0.8; P=0.01), from cervical cancer 2.5 (1.1 to 6.1; P=0.04), and from cerebrovascular disease 1.9 (1.2 to 3.1, P=0.009). By contrast, for women who had stopped use ⩾10 years previously there were no significant excesses or deficits either overall or for any specific cause of death.
Conclusion
Oral contraceptives seem to have their main effect on mortality while they are being used and in the 10 years after use ceases. Ten or more years after use ceases mortality in past users is similar to that in never users.
Key messagesThis 25 year follow up of 46 000 UK women found a decrease in mortality from ovarian cancer and an increase in mortality from circulatory diseases and cervical cancer among women were using oral contraceptives or had used them in the past 10 years10 or more years after stopping use mortality was similar in past users and never usersOral contraceptives seem to have their main effect on mortality mainly while they are being used and in the 10 years after stopping useThere is little evidence to suggest any persistent adverse effect 10 or more years after use of oral contraceptives ceases
PMCID: PMC27684  PMID: 9880284
14.  Impact of Cyclooxygenase Inhibitors in the Women's Health Initiative Hormone Trials: Secondary Analysis of a Randomized Trial 
PLoS Clinical Trials  2006;1(5):e26.
Objectives:
We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials.
Design:
The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6.
Setting:
The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States.
Participants:
The trials enrolled 27,347 postmenopausal women, aged 50–79 y.
Interventions:
We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.
Outcome Measures:
Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.
Results:
Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68–1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86–2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57–1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69–1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified.
Conclusions:
Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results.
Editorial Commentary
Background: As part of a set of studies known as the Women's Health Initiative trials, investigators aimed to find out whether providing postmenopausal hormone therapy (estrogen in the case of women who had had a hysterectomy, and estrogen plus progestin for women who had not had a hysterectomy) reduced cardiovascular risk as compared to placebo. Earlier observational studies had suggested this might be the case. The trials found that postmenopausal hormone therapy did not reduce cardiovascular risk in the groups studied. However, there was a concern that medication use outside the trial with nonsteroidal anti-inflammatory drugs (NSAIDs), and specifically the type of NSAID known as COX-2 inhibitors, could have affected the findings. This concern arose because it is known that COX-2 inhibition lowers levels of prostacyclin, a molecule thought to be beneficial to cardiovascular health, whereas estrogen increases prostacyclin levels. Evidence from randomized trials and observational studies has also shown that patients treated with some COX-2 inhibitors are at increased risk of heart attacks and strokes; the cardiovascular safety of other NSAIDs is also the focus of great attention. Therefore, the authors of this paper aimed to do a statistical exploration of the data from the Women's Health Initiative hormone trials, to find out whether NSAID use by participants in the trials could have affected the trials' main findings.
What this trial shows: In this reanalysis of the original data from the trials, the investigators found that the effects of hormone therapy on cardiovascular outcomes were similar among users and non-users of NSAIDs, confirming that use of these drugs did not significantly affect the results from the Women's Health Initiative hormone trials.
Strengths and limitations: The original hormone trials were large, appropriately randomized studies that enrolled a diverse cohort of participants. Therefore, a large number of cardiovascular events occurred in the groups being compared, allowing this subsequent analysis to be done. One limitation is that use of COX-2 inhibitors in the trial was low; therefore, the investigators were not able to specifically test whether COX-2 inhibitor use (as opposed to NSAID use generally) might have affected their findings.
Contribution to the evidence: The investigators did not set out specifically to evaluate the cardiovascular safety of particular medications in this study. Rather, they wanted to see if these NSAIDs could have modified the effects of the hormone therapy. The secondary analysis done here shows that the main findings from the Women's Health Initiative hormone trials were not significantly affected by use of NSAIDs outside the trial.
doi:10.1371/journal.pctr.0010026
PMCID: PMC1584256  PMID: 17016543
15.  Cervical cancer 
Clinical Evidence  2006;2006:0818.
Introduction
Worldwide, cervical cancer is the second most common cancer in women. The peak prevalence of infection is 20-30% in women aged 20-30 years, but in 80% of cases the infection resolves within 12-18 months. In the UK, incidence fell after introduction of the cervical-screening programme, to the current level of approximately 3200 cases and 1000 deaths a year. Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5-15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to manage early-stage cervical cancer? What are the effects of interventions to manage bulky early-stage cervical cancer? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: HPV vaccine for preventing cervical cancer and conisation of the cervix for microinvasive carcinoma (stage Ia1), neoadjuvant chemotherapy, radiotherapy, chemoradiotherapy, or different types of surgery for treating early stage and bulky early stage cervical cancer.
Key Points
Worldwide, cervical cancer is the second most common cancer in women. In the UK, incidence fell after the introduction of the cervical screening programme to the current level of approximately 3200 cases and 1000 deaths a year.About 80% of tumours are squamous type, and staging is based on the FIGO classification.Survival ranges from almost 100% 5-year disease-free survival for treated stage Ia disease to 5-15% in stage IV disease. Survival is also influenced by tumour bulk, age, and comorbid conditions.Development of cervical cancer is strongly associated with HPV infection, acquired mainly by sexual intercourse.The peak prevalence of infection is 20-30% in women aged 20-30 years, but in 80% of cases the infection resolves within 12-18 months.Other risk factors for cervical cancer include early onset of sexual activity, multiple sexual partners, long-term use of oral contraceptives, tobacco smoking, low socioeconomic status, immunosuppressive therapy, and micronutrient deficiency.
Vaccination against HPV is effective in preventing certain types of HPV infection, and at reducing rates of cervical intraepithelial neoplasia, but there has been insufficient long-term follow-up to assess effects on cervical cancer rates.
Conisation with adequate excision margins is considered effective for microinvasive carcinoma, and can preserve fertility; however, it is associated with an increased risk of preterm delivery and low birthweight. Conisation is often performed for Stage Ia1 disease, but evidence for its benefit is from observational studies only.
Radical trachelectomy plus lymphadenectomy can lead to similar long-term survival rates as radical hysterectomy, but with preserved fertility. Limited evidence shows that radical trachelectomy plus lymphadenectomy results in similar disease-free survival in women with early-stage cervical cancer compared with radical hysterectomy, but has higher intraoperative complications, and up to 8% recurrence of carcinoma.
Limited evidence shows that radiotherapy is as effective as surgery in early-stage disease. Overall and disease-free survival are similar after radiotherapy or radical hysterectomy plus lymphadenectomy, but radiotherapy is less likely to cause severe adverse effects.
Chemoradiotherapy improves survival compared with radiotherapy in women with bulky early-stage cervical cancer. Combined chemoradiotherapy improves overall and progression-free survival when used either before or after hysterectomy, but is associated with more haematological and gastrointestinal toxicity compared with radiotherapy alone.
The benefits of neoadjuvant chemotherapy plus surgery compared with radiotherapy alone are unknown.
PMCID: PMC2907636
16.  HYSTERECTOMY IS ASSOCIATED WITH LARGE ARTERY STIFFENING IN ESTROGEN-DEFICIENT POSTMENOPAUSAL WOMEN 
Menopause (New York, N.Y.)  2012;19(9):1000-1007.
Objective
Hysterectomy, with or without oophorectomy is associated with increased cardiovascular disease (CVD) risk due, in part, to an adverse CVD risk factor profile. Large artery stiffening, a biomarker of vascular aging, increases the risk for CVD. We determined whether hysterectomy with or without bilateral oophorectomy (BLO) is associated with arterial stiffening in healthy postmenopausal women.
Methods
We conducted a cross-sectional study including estrogen-deficient postmenopausal women who had a hysterectomy with ovarian preservation (N= 24; 59±1 year, mean±SE) or with BLO (N=21; 58±2 year), and had no hysterectomy/no BLO (N=58; 58±1 year). Arterial stiffness (arterial compliance and beta stiffness index) was measured by ultrasonography of the carotid artery.
Results
Carotid artery compliance was lower in women with hysterectomy alone and in women with hysterectomy with BLO compared to women with no hysterectomy (0.66±0.03 and 0.71±0.06 versus 0.89±0.03 mm2/mmHg×10−1, respectively, both P<0.05). There were no differences in traditional CVD risk factors (i.e., adiposity, blood pressure and fasted lipids and lipoproteins, glucose and insulin) between the groups. After adjustment for age, menopause duration, prior menopausal hormone therapy duration, parity, waist-to-hip ratio, systolic blood pressure and sex-hormone binding globulin, hysterectomy status remained a significant predictor of arterial compliance.
Conclusions
These results indicate that hysterectomy status (with or without BLO) is associated with greater arterial stiffening in estrogen-deficient postmenopausal women. The greater arterial stiffening with hysterectomy was not related to an adverse CVD risk profile. Large artery stiffening may be an important mechanism by which hysterectomy increases the risk of CVD in postmenopausal women.
doi:10.1097/gme.0b013e31825040f9
PMCID: PMC3428437  PMID: 22692329
vascular function; aging; menopause
17.  Conjugated Equine Oestrogen and Breast Cancer Incidence and Mortality in Postmenopausal Women with Hysterectomy: Extended Follow-up of the Women’s Health Initiative Randomised Trial 
The lancet oncology  2012;13(5):476-486.
Background
In contrast to many observational studies, women in the Women’s Health Initiative (WHI) trial randomised to oestrogen-alone had lower invasive breast cancer incidence than those assigned placebo. Influence of oestrogen use on breast cancer mortality has not been reported.
Methods
Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US centres into a randomized, double-masked, placebo-controlled trial evaluating oral conjugated equine oestrogen (0·625 mg/d). Women aged 50–79 years with prior hysterectomy, anticipated 3-year survival, and mammography clearance were randomized by a computerized, permuted block algorithm, stratified by age group and centre, to receive oestrogen or matching placebo. The trial was terminated early, in 2004, for an adverse effect on stroke. In extended follow-up through August 2009, we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumor characteristics, and mortality. Cox regression models were used to estimate intention-to-treat hazard ratios [HRs].
Findings
After a median 11.8 (interquartile range [IQR], 9·1 to 12·9) years of follow-up, conjugated equine oestrogen-alone use for a median of 5·9 (IQR, 2·5 to 7·3) years was associated with lower invasive breast cancer incidence compared to placebo (151 vs. 199 breast cancers; annualized rates, 0·27% vs. 0·35%; HR, 0·77; 95% confidence interval [CI], 0·62 to 0·95; P=0·02) with no difference (P=0·76) between intervention-phase (HR, 0·79; 95% CI, 0·61 to 1·02) and post-intervention effects (HR, 0·75; 95% CI: 0·51 to 1·09) ). Potential effect modification by benign breast disease (P=0·01) and family history of breast cancer (P=0·02) was observed. In the oestrogen-alone group fewer women died from breast cancer (6 vs.16 deaths; annualized rates 0·009% vs. 0·024%; HR, 0·37; 95% CI, 0·13 to 0·91; P=0.03) and fewer died from all causes after a breast cancer diagnosis (30 vs. 50 deaths; annualized rates, 0·046% vs. 0·076%; HR, 0·62; 95% CI, 0·39 to 0·9;, P=0·04).
Interpretation
Women with hysterectomy seeking relief of climacteric symptoms may be given reassurance regarding breast cancer influence of oestrogen use consistent with durations observed in this trial. However, these findings do not support oestrogen use for breast cancer risk reduction since this benefit may not apply to populations at higher risk.
Funding
US National Heart, Lung and Blood Institute. Wyeth provided study medications.
doi:10.1016/S1470-2045(12)70075-X
PMCID: PMC3412626  PMID: 22401913
menopausal hormone therapy; breast neoplasms; breast cancer mortality; prevention trial
18.  Effect of Hysterectomy With Ovarian Preservation on Ovarian Function 
Obstetrics and gynecology  2011;118(6):1271-1279.
Objective
To prospectively estimate the risk for earlier ovarian failure among women undergoing hysterectomy with ovarian preservation, as compared to women of similar age without hysterectomy.
Methods
A prospective cohort study was conducted among women aged 30 to 47 years undergoing hysterectomy without bilateral oophorectomy (n=406) and women with intact uteri (n=465). Blood samples and questionnaire data were obtained at baseline and annually for up to 5 years. Hazard ratios (HR) for ovarian failure, defined as follicle-stimulating hormone (FSH) levels 40 IU/L or higher, were calculated using Cox proportional hazards models.
Results
Ovarian failure occurred among 60 of the women with hysterectomy and 46 of the control women. Women undergoing hysterectomy were at nearly a twofold increased risk for ovarian failure as compared to women with intact uteri (HR=1.92, 95% confidence interval (CI) 1.29 – 2.86). The proportional hazards model further estimated that 14.8% of women with hysterectomy experienced ovarian failure after four years of follow-up compared to 8.0% of the control women. Risk for ovarian failure was greater for women who had a unilateral oophorectomy along with their hysterectomy (HR=2.93, 95% CI 1.57 – 5.49), but also was significantly increased for women who retained both ovaries (HR=1.74, 95% CI 1.14 – 2.65).
Conclusions
Increased risk of earlier ovarian failure is a possible consequence of premenopausal hysterectomy. While it is unresolved whether it is the surgery itself or the underlying condition leading to hysterectomy that is the cause of earlier ovarian failure, physicians and patients should take into account this possible sequela when considering options for treatment of benign conditions of the uterus.
doi:10.1097/AOG.0b013e318236fd12
PMCID: PMC3223258  PMID: 22067716
19.  Hormone replacement therapy: characteristics of users and non-users in a British general practice cohort identified through computerised prescribing records. 
STUDY OBJECTIVE--To assess the feasibility of recruiting a cohort of women, including long term users of postmenopausal hormone replacement therapy (HRT), through computerised general practice prescribing records, and to compare clinical and demographic characteristics of users and non-user controls. DESIGN--Cross sectional analysis of questionnaire data. SETTING--Subjects were recruited through 17 general practices in the Oxfordshire, south west Thames, and north west Thames regions that contributed to the VAMP Research Database. PARTICIPANTS--A total of 2964 women aged 45-64 years were identified. Altogether 1482 were long term (> 1 year) users of HRT and 1482 were non-user controls: 1037 (70%) of the users and 819 (55.3%) of the controls agreed to participate and provided questionnaire data. MAIN RESULTS--Users of HRT were more likely to have undergone hysterectomy than controls. Most women with a history of hysterectomy used unopposed oestrogen, while those with intact uteri generally used a combination of oestrogen and a progestagen. Among women who had undergone hysterectomy, HRT users did not differ significantly from controls over a range of demographic and clinical characteristics but they were more likely to be past users of oral contraceptives. Among women with intact uteri, users were similar to controls in terms of reported clinical characteristics, but were of higher social class and were more likely to be past users of oral contraceptives and to have had a mammogram after the age of 50. Compared with the general population, all categories of women recruited to the study were of higher social class and exhibited more health conscious behaviours. CONCLUSIONS--Electronic general practice prescribing records provide a feasible and efficient method for recruiting women to a cohort of HRT. Women who agreed to participate in this study were not representative of the general population, emphasising the importance of internal controls in such a study. Among participants, HRT users who had not undergone hysterectomy showed evidence of better health than non-users on some dimensions. In the whole sample, however, there were no appreciable differences in social class and self reported health indicators between users and controls.
PMCID: PMC1060127  PMID: 7650462
20.  A randomised trial comparing endometrial resection and abdominal hysterectomy for the treatment of menorrhagia. 
BMJ : British Medical Journal  1991;303(6814):1362-1364.
OBJECTIVE--To determine the advantages and disadvantages of endometrial resection and abdominal hysterectomy for the surgical treatment of women with menorrhagia. DESIGN--Randomised study of two treatment groups with a minimum follow up of nine months. SETTING--Royal Berkshire Hospital, Reading. SUBJECTS--51 of 78 menorrhagic women without pelvic pathology who were on the waiting list for abdominal hysterectomy. TREATMENT--Endometrial resection or abdominal hysterectomy (according to randomisation). Endometrial resections were performed by an experienced hysteroscopic surgeon; hysterectomies were performed by two other gynaecological surgeons. MAIN OUTCOME MEASURES--Length of operating time, hospitalisation, recovery; cost of surgery; short term results of endometrial resection. RESULTS--Operating time was shorter for endometrial resection (median 30 (range 20-47) minutes) than for hysterectomy (50 (39-74) minutes). The hospital stay for endometrial resection (median 1 (range 1-3) days) was less than for hysterectomy (7 (5-12) days). Recovery after endometrial resection (median 16 (range 5-62) days) was shorter than after hysterectomy (58 (11-125) days). The cost was 407 pounds for endometrial resection and 1270 pounds for abdominal hysterectomy. Four women (16%) who did not have an acceptable improvement in symptoms after endometrial resection had repeat resections. No woman has required hysterectomy during a mean follow up of one year. CONCLUSION--For women with menorrhagia who have no pelvic pathology endometrial resection is a useful alternative to abdominal hysterectomy, with many short term benefits. Larger numbers and a longer follow up are needed to estimate the incidence of complications and the long term efficacy of endometrial resection.
PMCID: PMC1671634  PMID: 1760601
21.  Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies 
PLoS Medicine  2013;10(7):e1001492.
Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors.
Please see later in the article for the Editors' Summary
Background
Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.
Methods and Findings
Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.
Conclusions
These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer.
Why Was This Study Done?
Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer.
What Did the Researchers Do and Find?
Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model.
What Do These Findings Mean?
These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492.
This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer;
Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site
Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer
The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer
doi:10.1371/journal.pmed.1001492
PMCID: PMC3728034  PMID: 23935463
22.  Hysterectomy and socioeconomic position in Rome, Italy 
Study objective: There exists conflicting evidence regarding the higher risk of hysterectomy among women of a lower educational and economic level. This study aims to assess whether in Italy socioeconomic level is related to hysterectomy undertaken for different medical reasons.
Design: An area based index was used to assign socieconomic status (SES; four levels defined) to 3141 women (aged 35 years or older) who underwent a hysterectomy in 1997 and were residing in Rome. Data were taken from hospital discharge records. Direct age standardised hospitalisation rates by SES level were calculated for overall hysterectomies and for those performed for either malignant or non-malignant causes. Statistical differences were detected using the ratios of standardised rates and the test for linear trend.
Main results: The hysterectomy rate was 36.7 per 10 000 women aged 35 years or more. Hysterectomy for uterine leiomyoma accounted for 41% of all operations and was more frequent among women aged 35–49 years than for those aged 50 years or more (crude rates: 28.6 and 7.7 per 10 000, respectively). The risk of hysterectomy was 35% higher for the lowest SES group, compared with the highest group. No association was found between SES and hysterectomy rates for malignant causes, although less affluent women in age group 35–49 years had 87% higher risk of hysterectomy compared with most affluent women. The inverse association between SES and hysterectomy rates attributable to non-malignant causes was statistically significant for women aged 35–49 years but not for those aged 50 years or more.
Conclusions: The inverse relation between hysterectomy and SES is largely attributable to benign disorders of the uterus, namely leiomyoma and prolapse. More affluent women may have a greater uptake of less invasive techniques for removing uterine leiomyoma compared with less affluent women, who are more likely to undergo unnecessary hysterectomies irrespective of their reproductive age.
doi:10.1136/jech.56.6.461
PMCID: PMC1732169  PMID: 12011206
23.  Risk Factors for Pelvic Floor Repair After Hysterectomy 
Obstetrics and gynecology  2009;113(3):601-608.
Objective
Having demonstrated that prior history of prolapse was a risk factor for pelvic floor repair procedures after hysterectomy, the objective of this study was to assess medical risk factors for pelvic floor repair after hysterectomy.
Methods
Using the Rochester Epidemiology Project database of 8,220 Olmsted County, Minnesota women who had hysterectomy for benign indications in 1965-2002, we conducted a nested case-control study in 144 pairs, comparing women who underwent pelvic floor repair after hysterectomy (cases) to controls matched for known risk factors (ie, age, pelvic floor disorders at baseline, year and type of hysterectomy, and pelvic floor repair during hysterectomy).
Results
The median duration between hysterectomy and pelvic floor repair was 13 years. Chronic pulmonary disease (odds ratio [OR] 14.3; 95% CI 1.2 to 178) but not obstetric history, obesity, indication for hysterectomy, or chronic constipation was associated with an increased risk of pelvic floor repair after hysterectomy. Between the hysterectomy and subsequent pelvic floor repair, overall pelvic organ prolapse severity changed by 1 grade or less in 54 cases (38%, Group A) but increased by 2 or more grades in 72 cases (50%, Group B). In Group A, but not Group B, uterine prolapse (OR 25; 95% CI 2.1 to 300) and chronic pulmonary disease (OR 22; 95% CI 1.5 to 328) at baseline remained risk factors for pelvic floor repair after hysterectomy.
Conclusion
In this matched case-control study, chronic pulmonary disease was the only risk factor for pelvic floor repair after hysterectomy for benign indications, underscoring the need to address pulmonary status prior to surgery.
doi:10.1097/AOG.0b013e3181998998
PMCID: PMC2720564  PMID: 19300323
24.  Timing of menarche, childbearing and hysterectomy risk 
Maturitas  2008;61(4):317-322.
Objectives
To examine the associations of age at menarche, timing of first birth and parity with hysterectomy rates; to investigate whether these associations were independent of each other and other potential confounders and varied by reason for hysterectomy.
Methods
Women from the Medical Research Council National Survey of Health and Development, a cohort followed prospectively since birth in March 1946 across England, Scotland and Wales, were studied. Survival analyses were used to assess the relationships between reproductive characteristics and hysterectomy.
Results
Age at menarche was inversely associated with hysterectomy rates (adjusted Hazard Ratio for hysterectomy associated with a 1 year increase in menarche = 0.85 (95% CI: 0.77–0.95)). Parity was also associated with hysterectomy; women with ≥3 children experienced higher rates of hysterectomy than women with 1–2 children, who themselves experienced higher rates than nulliparous women. The associations of parity and age at menarche with hysterectomy were independent of each other and potential confounders. The association between age at menarche and hysterectomy was stronger for hysterectomies performed for fibroids than for other reasons.
Conclusions
Our findings suggest that age at menarche is most likely acting to influence hysterectomy risk through its association with lifetime oestrogen exposure whereas parity is most likely acting through an effect on decision-making processes. This highlights the importance of considering both biological and social pathways to hysterectomy and confirms that medical need is not the only factor which needs to be considered when making treatment decisions for gynaecological problems.
doi:10.1016/j.maturitas.2008.09.025
PMCID: PMC3500690  PMID: 19013032
Age at menarche; Parity; Age at first birth; Hysterectomy; Birth cohorts
25.  Health status of users of hormone replacement therapy by hysterectomy status in Western Australia 
Study objectives: To compare the demographic, behavioural, and biological correlates of use of hormone replacement therapy (HRT) in women with an intact uterus and women who have undergone hysterectomy.
Design: Cross sectional analysis of data from the Busselton Health Study and the 1994 Healthway-National Heart Foundation Risk Factor Survey.
Setting: Busselton and Perth, Western Australia, 1994.
Participants: 2540 women aged 35–79 years.
Main outcome measures: Demographic, behavioural, and biological correlates of use of HRT by hysterectomy status.
Results: In women with an intact uterus, after adjustment for age and place of residence, current use of HRT was significantly associated with having a professional level of occupation, ever use of alcohol, having a history of smoking, and a lower body mass index. Current users of HRT had significantly lower levels of total cholesterol and higher levels of triglycerides than non-users. In women who had undergone hysterectomy, the only non-biological characteristic associated with use of HRT was having a history of smoking. Current users of HRT had lower levels of systolic blood pressure, lower levels of LDL cholesterol, higher levels of HDL cholesterol, and higher levels of triglycerides. The association between use of HRT and participation in exercise, level of systolic blood pressure, level of HDL cholesterol, and total/HDL cholesterol ratio varied significantly by hysterectomy status. After adjustment for age and place of residence, the mean levels of systolic and diastolic blood pressure, body mass index, waist/hip ratio, LDL cholesterol, and total/HDL cholesterol ratio were highest in women who had undergone hysterectomy and were not using HRT.
Conclusions: Demographic/behavioural and biological correlates of use of HRT varied depending on hysterectomy status. Demographic and behavioural characteristics were more important as selection factors for use of HRT in women with an intact uterus than in women who had undergone hysterectomy. Women who had undergone hysterectomy and were not using HRT had a significantly worse profile for CHD than did women with an intact uterus. These results indicate that any bias in estimates of the protective effect of HRT on risk of CHD in observational studies is likely to depend on the prevalence of hysterectomy within the study population. Hysterectomy status needs to be taken into account in any studies that investigate the effect of HRT on risk of CHD.
doi:10.1136/jech.57.4.294
PMCID: PMC1732422  PMID: 12646547

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