To mark World Menopause Day on 18th October, the International Menopause Society has published a major review of cancer during and after the menopause, and asks women and their doctors to take appropriate precautions to minimise cancer risk.

Full Paper

Gompel A, Baber RJ, de Villiers TJ, Huang KE, Santen RJ, Shah D, Villaseca P, Shapiro S. Oncology in midlife and beyond. Climacteric. 2013 Oct;16(5):522-35. doi: 10.3109/13697137.2013.823539. Epub 2013 Aug 9.

Oncology in midlife and beyond - (personal use only)298.78 KB

IMS members react to the recent JAMA paper

15 October, 2013

Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. A total of 27,347 postmenopausal women aged 50–79 years were enrolled at 40 US centers to the Women's Health Initiative trial [1]. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/day) plus medroxyprogesterone acetate (MPA; 2.5 mg/day) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/day) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE + MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. During the CEE + MPA intervention phase, the numbers of coronary heart disease (CHD) cases were 196 for CEE + MPA vs. 159 for placebo (hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.95–1.45) and 206 vs. 155, respectively, for invasive breast cancer (HR 1.24; 95% CI 1.01–1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥ 65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated post-intervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE + MPA vs. 323 for placebo; HR 1.28; 95% CI 1.11–1.48). The risks and benefits were more balanced during the CEE-alone intervention with 204 CHD cases for CEE-alone vs. 222 cases for placebo (HR 0.94; 95% CI 0.78–1.14) and 104 vs. 135, respectively, for invasive breast cancer (HR 0.79; 95% CI 0.61–1.02); cumulatively, there were 168 vs. 216, respectively, cases of breast cancer diagnosed (HR 0.79; 95% CI 0.65–0.97). Results for other outcomes were similar to CEE + MPA. Neither regimen affected all-cause mortality. For CEE-alone, younger women (aged 50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index. Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE + MPA ranged from 12 excess cases for ages of 50–59 years to 38 for ages of 70–79 years; for women taking CEE-alone, from 19 fewer cases for ages of 50–59 years to 51 excess cases for ages of 70–79 years. Quality-of-life outcomes had mixed results in both trials. In conclusion, findings from the intervention and extended post-intervention follow-up of the two WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Comment

Comment I

There are several key points to the newest WHI manuscript [1], the largest compendium of WHI data published in one place to date. Importantly, the WHI investigators issue the following warning on page 1354 under 'Statistical Analysis': 'The p values do not adjust for multiple outcomes, sequential monitoring, or multiple subgroup comparisons due to the large number of tests conducted; therefore, the p values should be interpreted cautiously.' As Figures 2 and 4 show, even in the absence of the foregoing appropriate adjustments, almost no adverse outcomes are statistically significant, and, as the original publications from the WHI have shown for breast cancer, stroke and all of the other adverse outcomes, that, when adjusted for multiple outcomes and sequential monitoring according to the a-prioridefined statistic, all of these outcomes are not statistically significantly different between hormone therapy (HT) and placebo in both the CEE + MPA and CEE trials [2, 3]. The one exception is the venous thromboembolic event outcome in the CEE + MPA trial. In other words, all of the adverse outcomes from the WHI HT trials are not statistically significantly different between HT and placebo (except for the one exception noted previously) when analyzed across all women randomized to these trials (average age 64 years and average time from menopause > 10 years). Further, this newest WHI publication again validates that not only are all of the adverse outcomes non-significant, but they are similar to the types and magnitude of adverse events reported with other commonly used medications, that is, rare (< 1/1000 additional events per year of therapy) [2, 3].

The second important fact to realize from this newest WHI publication is that Figures 5 and 6 show that all outcomes are reduced with CEE relative to placebo in women who are 50–59 years old when randomized. Pulmonary embolism and hip fracture, which show three additional events per 10,000 women per year of therapy, are the only exceptions to the consistent reduction in outcomes. As such, the data in these figures do not support the conclusion of the manuscript that HT should not be used for chronic disease prevention. Some may argue that these are subgroup analyses and therefore should be ignored. However, if this is the case, then no statement concerning chronic disease prevention can be made based on the WHI data except for women over all ages, the majority of whom are well beyond the age in which HT is initiated. Women require HT and HT is initiated predominantly in women < 60 years of age, typically in the perimenopause or early menopause, when the data support clear benefit relative to risk, as shown in a recent 10-year randomized trial of such women [4]. In other words, the WHI has no relevance to clinical practice as presented across the entire cohort of women; its importance is in showing a reduction of coronary heart disease, breast cancer, stroke and, most importantly, total mortality by 30% with CEE as well as CEE + MPA therapy in women who were initiated on such therapy when < 60 years of age. Based on the WHI data, it has recently been estimated that 50,000–90,000 women over the last decade have needlessly died by avoiding the use of HT [5]. This estimate appears to be consistent with the inexplicable worsening mortality rate of women in the United States relative to men from 1992 to 1996 (pre-WHI) relative to 2002–2006 (post-WHI) [6].

It must be emphasized that WHI data cannot inform about chronic disease prevention since benefits and risks of HT when initiated in a 70–80-year-old women cannot be assumed to equate to the benefits and risks of women 20–30 years after initiating HT at 50–60 years of age. The contrary, however, is that which follows known preventive therapy logic in which risk is reduced initially and is followed by reduction in adverse events, such as bone fracture prevention. There is absolutely no evidence to indicate that HT operates differently from this well-known paradigm of chronic disease prevention. The fact that '…the risk reductions dissipated post-intervention', as stated on page 1366 of the newest WHI manuscript, clearly indicates that chronic disease prevention will only be appreciated with continuous HT, as seen with the prevention of bone fractures.

Howard N. Hodis
Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, USA


Comment II

The recent updated report of the WHI study (follow-up of 13 years) did not add anything of importance to help practitioners who care for postmenopausal women [1]. It must be emphasized again that the methodology followed by the WHI study does not in any way reflect what is meant by good clinical practice. This is their capital error. Let it not be forgotten that all enrolled patients were treated with the same medication and dosage irrespective of their age and tolerance. Furthermore, the estrogen (CEE) and the progestogen (MPA) used were not the best choices since they may cause important side-effects that are rare with 17β-estradiol and natural progesterone, as mostly used in Europe. Past observational studies and the recent KEEPS study, much closer to good clinical practice, did not support most of the conclusions of the WHI investigators. The only important observation is that the good candidates for hormone therapy are women younger than 60 years of age or within 10 years after the menopause. There is nowadays a general consensus that CEE + MPA should not be first-choice medications and that the more one mimics physiology the better, i.e. 17β-estradiol and progesterone itself, or dydrogesterone. The parenteral route for the administration of estradiol seems to be safer. WHI investigators, with their unbalanced conclusions, have already caused much damage to women who have been deprived of appropriate and needed hormone therapy and thus of the resulting preventive effects at the level of the cardiovascular system and bones.

Manuel Neves-e-Castro
Lisbon, Portugal

References

1. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative Randomized Trials. JAMA 2013;310:1353-68. 
http://www.ncbi.nlm.nih.gov/pubmed/24084921

2. Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. 1. Comparison of therapeutic efficacy. J Am Geriatr Soc 2013;61:1005-10.
ttp://www.ncbi.nlm.nih.gov/pubmed/23414520

3. Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. 2. Comparative risks. J Am Geriatr Soc 2013;61:1011-18.
http://www.ncbi.nlm.nih.gov/pubmed/23692449

4. SchierbeckLL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345:e6409.
http://www.ncbi.nlm.nih.gov/pubmed/23048011

5. Sarrel PM, Njike VY, Vinante V, et al. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50–59 years. Am J Public Health 2013;103:1583-8
http://www.ncbi.nlm.nih.gov/pubmed/23865654

6. Kindig DA, Cheng ER. Even as mortality fell in most US counties, female mortality nonetheless rose in 42.8% of counties from 1992 to 2006. Health Affairs 2013;32:451-8.
http://www.ncbi.nlm.nih.gov/pubmed/23459723

23 September, 2013

Another potential 'bomb' exploded recently, with the online publication of a study which showed that common therapies for controlling blood pressure may have an effect on the risk for breast cancer [1]. The study, which was observational and retrospective, was based on interviews with breast cancer patients and comparable healthy controls in Seattle, USA. Women were asked whether they used antihypertensive medications and, if they did, what type, when, and for how long. The cohort included 880 women with invasive ductal breast cancer, 1027 women with invasive lobular breast cancer, and 856 women with no cancer who served as controls. Results showed that those currently taking calcium-channel blockers for more than 10 years had about 2.5 times the risk for breast cancer (both ductal and lobular) compared to healthy women, whereas the use of angiotensin II antagonists was associated with a non-significant decrease in risk, and diuretics or beta-blockers were neutral in this respect. Shorter periods of use were not associated with a change in breast cancer risk.

May not be enough to keep weight stable

16 September, 2013

Whenever one talks about the need to keep optimal weight in order to reduce cardiovascular risk and other health hazards, one will always quote the mantra – eat healthy and stay fit, which means keeping the desired balance between caloric intake and energy expenditure. The standard equation says that 7000 kcal equal 1 kg of fat, so, if the energy balance over a period of time points is (-)7000 kcal, this negative figure should also be expressed while standing on the scale, which should show 1 kg reduction in weight. All guidelines and recommendations are based on this formulation, and the scenario of failure to maintain or reduce weight despite keeping the instructions is attributed solely to poor adherence to the intervention program. Now it seems that there may be other explanations. A study published recently in Science examined mice that were put in a system that could accurately measure both their caloric intake and energy expenditure [1]. Two groups were compared: normal mice and those with deletion of melanocortin 2 receptor accessory protein 2 (MRAP2), which are known to develop severe obesity at a young age. Even when fed the same amount of chow, null mice gained more weight than did wild-type mice. Only when the amount of food intake in null mice was further restricted to 10% (females) and 13% (males) less than that of wild-type mice was there equivalent weight gain. This was the case while mice were young but, at later stages of their life, the null mice demonstrated overt hyperphagia and associated weight gain.

26 August 2013

Sowers and colleagues have investigated potential associations between changes in bone resorption during the menopause transition and reproductive hormones, body mass index (BMI) and ethnicity [1]. Urinary type I collagen N-telopeptide (NTX), estradiol, and follicle stimulating hormone (FSH) levels were measured annually for up to 8 years spanning the menopause transition in 918 African-American, Chinese, Japanese, or Caucasian women. Urinary NTX began to increase sharply about 2 years before the final menstrual period (FMP), reaching its peak level about 1–1.5 years after the FMP. NTX levels declined modestly from 2–6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began to increase rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI < 25 kg/m2 and smallest in women with BMI > 30 kg/m2. Increases in NTX were greatest in Japanese women and smallest in African-Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI. During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss.

12 August, 2013

Meningiomas, which arise from tissues that cover the brain and spinal cord, represent about a fifth of all brain tumors, and they affect women more often than men [1]. The reason for a female predominance is not known, although most meningiomas express receptors for progesterone and some also express estrogen or androgen receptors [2]. Most arise from the arachnoid villi in association with the dura mater or intracranial venous sinuses. Meningiomas are typically slow growing and may compress the brain, but they usually do not invade neural tissues or metastasize to distant sites. Many meningiomas are asymptomatic, discovered only as incidental findings at autopsy or on brain imaging studies performed for some other reason (e.g. ordered because of headache or light-headedness) [3].

In a nationwide case-control study, Danish investigators recently reported associations between menopausal hormone therapy (HT) and meningioma [4]. Their findings, which are largely consistent with other observational research, are also notable from the perspectives of interpretation, perception, and validity.

29 July, 2013

Although oral bisphosphonates are highly effective in preventing fractures, some patients will still suffer a fracture while on treatment. In fact, it is important to explain to the patient that any anti-fracture treatment is indeed capable of reducing, but not aborting the risk for fractures. The following study from Spain quantified the remaining risk of fracture while on bisphosphonate therapy [1].

The SIDIAP database was searched to identify new users of oral bisphosphonates in 2006–2007. SIDIAP includes pharmacy invoice data and primary-care electronic medical records for a representative 5 million people in Catalonia (Spain). Exclusion criteria were: Paget disease, < 40 years of age, and any anti-osteoporosis treatment in the previous year. A priori defined risk factors included age, gender, body mass index, vitamin D deficiency, smoking, alcohol drinking, pre-existing co-morbidities, and medications. Fractures were considered if they appeared after at least 6 months after treatment initiation. Fractures while on treatment were defined as those occurring among participants persisting for at least 6 months and with an overall high compliance (medication possession ratio ≥ 80%). Only 7449/21,385 (34.8%) participants completed > 6 months of therapy. Incidence of 'fracture while on treatment' was 3.4/100 person-years (95% confidence interval (CI) 3.1–3.7). Predictors of these among patients persisting and adhering to treatment included: older age (sub-hazard ratio (SHR) for 60 to < 80 years 2.18; 95% CI 1.70–2.80; for ≥ 80 years, SHR 2.5; 95% CI 1.82–3.43), previous fracture (SHR 1.75; 95% CI 1.39–2.20 and SHR 2.49; 95% CI 1.98–3.13 in the last 6 months and longer, respectively), underweight (SHR 2.11; 95% CI 1.14–3.92), inflammatory arthritis (SHR 1.46; 95% CI 1.02–2.10), use of proton pump inhibitors (SHR 1.22; 95% CI 1.02–1.46), and vitamin D deficiency (SHR 2.69; 95% CI 1.27–5.72). Thus, even among high compliers, 3.4% of oral bisphosphonate users will fracture every year. Older age, underweight, vitamin D deficiency, proton pump inhibitor use, previous fracture and inflammatory arthritides are associated with increased fracture risk.

22 July, 2013: 

Sarrel and colleagues [1] calculated the mortality toll due to avoiding estrogen in hysterectomized women aged 50–59 between 2002 and 2011. The calculation was motivated by the Women's Health Initiative (WHI) estrogen-only trial report in 2011 [2] which indicated an excess mortality in women in this age group who did not take estrogen, i.e.. received placebo. The excess mortality was 13/10,000 women/year. Twelve of the 13 deaths were due to cardiovascular disease. An increase in deaths from invasive breast cancer was also seen in the women who received placebo [3]. The Yale research team calculated the best point estimates for the total excess mortality for hysterectomized women aged 50–59 in the United States from 2002 through 2011 to be between 40,292 and 48,835.

A calculation was made for each of the years using the excess mortality rate of 13/10,000/year, annual US Census population estimates, hysterectomy rates as reported in the peer-reviewed literature, and percent decline in estrogen use each year compared to 2001, as reported in the WHI paper [2]. Adjustment was made for different pre-2002 rates of estrogen use depending on whether or not ovaries had been retained at the time of hysterectomy. The best point estimates represent the aggregate of all the years taking into account all the assumptions.

8 July, 2013

Erekson and colleagues recently published in the journal Menopause on their development of a Vulvovaginal Symptoms Questionnaire (VSQ) to determine the symptoms, emotions, life impact, and sexual impact of vulvovaginal symptoms on postmenopausal women [1]. They performed a number of validation tests which confirmed the utility of the questionnaire. Postmenopausal vulvovaginal symptoms include dryness, burning, pruritus, and dyspareunia. Vulvovaginal symptoms are common and have been reported by 9.6–44.4% of postmenopausal women. The authors found the VSQ to be a reliable and internally consistent instrument for measuring vulvovaginal symptoms in postmenopausal women. The authors demonstrated a reasonable validity of the VSQ, particularly in the absence of a gold standard for measuring vulvovaginal symptoms.

17 June, 2013

Once in 5 years, the American Cancer Society publishes its updated guidelines on nutrition and physical activity in the context of cancer prevention [1]. Among the detailed advice is the following quote: 'Limit consumption of sugar-sweetened beverages such as soft drinks, sports drinks, and fruit-flavored drinks.' How this general phrasing relates to specific cancer types is discussed below, and a recent study serves as a good starting point [2]. The investigators evaluated the impact of dietary intake of sugary foods and beverages, as well as added sugar and total sugar on endometrial cancer risk in a population-based, case-control study, including 424 cases and 398 controls. Participants completed an interview and food frequency questionnaire and provided self-recorded waist and hip measurements. Women in the highest quartile of added sugar intake had significantly increased endometrial cancer risk (OR 1.84, 95% CI 1.16–2.92). Among women with waist-to-hip ratio ≥ 0.85, risk was significantly higher for the highest versus lowest tertile of added sugar intakes (OR 2.50, 95% CI 1.38–4.52). The association with added sugar also became stronger when analyses were restricted to never users of hormone replacement therapy (OR 2.03, 95% CI 1.27–3.26, for highest versus lowest tertile). There was little evidence of effect modification by body mass index or physical activity.