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Updated IMS recommendations onpostmenopausal hormone therapy andpreventive strategies for midlife health D. W. Sturdee and A. Pines on behalf of the International Menopause Society Writing Group Writing Group: D. F. Archer, R. J. Baber, D. Barlow, M. H. Birkha¨user, M. Brincat, L. Cardozo, T. J. de Villiers,M. Gambacciani, A. A. Gompel, V. W. Henderson, C. Kluft, R. A. Lobo, A. H. MacLennan, J. Marsden, R. E. Nappi,N. Panay, J. H. Pickar, D. Robinson, J. Simon, R. L. Sitruk-Ware and J. C. Stevenson Menopause Societies from all continents participated in thediscussions.
The past decade has seen marked fluctuations in opinions The 2011 revision of the IMS Recommendations is concerning the merits and risks of postmenopausal hormone published when the atmosphere around the issue of post- replacement therapy (HRT). In July 2002, menopause menopausal HRT is much more rational. The pendulum management faced a major turning point when the first data swung back from its peak negative sentiment following more from the Women’s Health Initiative (WHI) trial were released.
detailed data from the WHI study that demonstrated the This study was categorized as a primary prevention trial for importance of the age at initiation and the good safety profile coronary heart disease. However, the mean age at recruitment of HRT in women younger than 60 years. Since these were was 63 years, when menopausal symptoms have usually exactly the IMS views expressed in the previous Recommen- finished and HRT is rarely started, but this important dations, the current update is similar in principle to the 2007 difference from common clinical practice was not acknowl- version, but with the additional clinical data where needed. It edged at that time. Instead, WHI investigators concluded that has been produced by a small Writing Group of experts, and HRT was not cardioprotective and that its risk–benefit ratio not from a formal workshop, but is the considered view of the did not favor the use of postmenopausal hormones for IMS on the principles of HRT in the peri- and postmenopausal prevention of chronic diseases. As a result, there was a periods. Throughout the Recommendations, the term HRT dramatic change in prescription habits following recommen- will be used to cover therapies including estrogens, progesto- dations to reserve HRT for very symptomatic women, and to gens, combined therapies, androgens and tibolone. The IMS is limit its use to the ‘shortest duration needed’ and to ‘the aware of the geographical variations related to different lowest effective dosage’. This was the atmosphere in which the priorities of medical care, different prevalence of diseases, and International Menopause Society (IMS) initiated a Workshop country-specific attitudes of the public, the medical commu- held in Vienna (December 2003) and produced the subsequent nity and the health authorities toward menopause manage- IMS Position Paper resulting from the Workshop discussions.
ment, different availability and licensing of products, all of Basically, the IMS did not accept some interpretations which may impact on HRT. These Recommendations and the attributed to the WHI results and, being independent of local subsequent key messages therefore give a global and simple or regional constraints imposed by official health authorities, overview that serves as a common platform on issues related called for a more balanced approach to the scientific data.
to the various aspects of hormone treatment, which could be Because additional information has been accumulated from easily adapted and modified according to local needs.
both arms of the WHI study, from observational trials andfrom other studies during the following years, the first IMSStatement was updated in 2007, enlarging its scope to menopause management and adult women’s health in general.
This revised Statement was formulated in a Workshop held in Consideration of HRT should be part of an overall strategy Budapest in February 2007, in which 30 experts from the including lifestyle recommendations regarding diet, exercise, various fields of menopause medicine presented the latest smoking cessation and safe levels of alcohol consumption for information and delegates from 60 National and Regional maintaining the health of peri- and postmenopausal women.
Correspondence: Dr D. W. Sturdee, International Menopause Society, PO Box 687, Wray, Lancaster LA2 8LD, UK RECOMMENDATIONSª 2011 International Menopause SocietyDOI: 10.3109/13697137.2011.570590 Updated IMS recommendations on postmenopausal hormone therapy HRT must be individualized and tailored according to but not at levels that stimulate the endometrium, and so symptoms and the need for prevention, as well as personal concurrent progestogen is not required. Direct delivery of and family history, results of relevant investigations, the progestogen to the endometrial cavity from the vagina or by woman’s preferences and expectations. The risks and benefits an intrauterine system does provide endometrial protection of HRT differ for women during the menopause transition and may cause less systemic progestogenic effects than other HRT includes a wide range of hormonal products and Androgen replacement should be reserved for women routes of administration, with potentially different risks and with clinical signs and symptoms of androgen insufficiency.
benefits. Thus, the term ‘class effect’ is confusing and Androgen replacement often has significant beneficial effects inappropriate. However, evidence regarding differences in in women with bilateral oophorectomy or adrenal failure, risks and benefits between different products is limited.
particularly on health-related quality of life and sexual function.
Women experiencing a spontaneous or iatrogenic meno- pause before the age of 45 years and particularly before 40years are at higher risk for cardiovascular disease and osteoporosis and may be at increased risk of affectivedisorders and dementia. Use of HRT may reduce these risks but the evidence for this is limited. HRT may reducesymptoms and preserve bone density and is advised at least HRT remains the most effective therapy for vasomotor symptoms and urogenital atrophy. Other menopause-related Counselling should convey the benefits and risks of HRT in complaints, such as joint and muscle pains, mood swings, clear and comprehensible terms, e.g. as absolute numbers sleep disturbances and sexual dysfunction (including reduced rather than, or in addition to, percentage changes from libido) may improve during HRT. Quality of life and sexual baseline expressed as a relative risk. This allows a woman and function may also improve. The administration of individua- her physician to make a well-informed decision about HRT.
lized HRT (including androgenic preparations when appro- Written information about risks and benefits as well as priate) may improve both sexuality and overall quality of life.
HRT should not be recommended without a clear indica- tion for its use, i.e. significant symptoms or physical effects of Women taking HRT should have at least an annual consul- HRT is effective in preventing bone loss associated with the tation to include a physical examination, update of medical menopause and decreases the incidence of all osteoporosis- and family history, relevant laboratory and imaging investiga- related fractures, including vertebral and hip fractures, even in tions, a discussion on lifestyle, and strategies to prevent or women not at high risk of fracture. Based on evidence of reduce chronic disease. There is currently no indication for effectiveness, cost and safety, HRT can be considered as one increased mammographic or cervical smear screening.
of the first-line therapies for the prevention and treatment of There are no reasons to place mandatory limitations on the osteoporosis in postmenopausal women, younger than duration of HRT. Whether or not to continue therapy should 60 years, with an increased risk of fracture. The initiation of be decided at the discretion of the well-informed woman and HRT for the sole purpose of the prevention of fractures after her health professional, dependent upon the specific goals and the age of 60 years is not recommended. Continuation of HRT an objective estimation of ongoing benefits and risks.
after the age of 60 years for the sole purpose of the prevention Dosage should be titrated to the lowest effective dose.
of fractures should take into account the possible long-term Lower doses of HRT than have been used previously may effects of the specific dose and method of administration of reduce symptoms sufficiently and maintain quality of life for HRT, compared to other proven non-hormonal therapies.
many women. Long-term data on lower doses regarding The protective effect of HRT on bone mineral density fracture or cancer risks and cardiovascular implications are (BMD) declines after cessation of therapy at an unpredictable rate, although some degree of fracture protection may remain In general, progestogen should be added to systemic after cessation of HRT. If the patient is still considered at risk estrogen for all women with a uterus to prevent endometrial for fracture after cessation of HRT, additional therapy with hyperplasia and cancer. However, natural progesterone and proven bone-sparing medication should be given.
some progestogens have specific beneficial effects that could Evidence of the fracture-protective effect of HRT is limited justify their use besides the expected actions on the to standard dosages of conjugated equine estrogen (CEE) and endometrium, e.g. the well-documented blood pressure- medroxyprogesterone acetate (MPA), given by the oral route.
lowering effect of drospirenone. Also, progestogens may not Evidence for protection against loss of BMD is available be alike in regard to potential adverse metabolic effects or for lower than standard doses in oral (CEE and 17b-estradiol) associated breast cancer risk when combined with long-term and transdermal (17b-estradiol) administration. Tibolone, estrogen therapy. Low-dose vaginal estrogens, administered a synthetic molecule that has affinity for the estrogen, for the relief of urogenital atrophy, are systemically absorbed, progesterone and androgen receptors, has proven efficacy Updated IMS recommendations on postmenopausal hormone therapy against vertebral and non-vertebral fractures. The selective thromboembolism (pulmonary embolism or deep vein throm- estrogen receptor modulators (SERMs), raloxifene, lasofox- ifene and bazedoxifene, reduce the risk of vertebral fracture inpostmenopausal women with or without prevalent vertebralfractures.
The incidence of breast cancer varies in different countries.
Therefore, currently available data may not be applicableeverywhere. The degree of association between breast cancer Cardiovascular disease is the principal cause of morbidity and and postmenopausal HRT remains controversial.
mortality in postmenopausal women. Major primary preven- Women should be reassured that the possible increased risks tion measures (besides smoking cessation and diet control) are of breast cancer associated with HRT are small (less than weight loss, blood pressure reduction, regular exercise and 0.1% per annum, or an incidence of 51.0 per 1000 women diabetes and lipid control. HRT has the potential for per year of use), and less than the increased risks associated improving the cardiovascular risk profile through its beneficial with common lifestyle factors such as obesity and alcohol effects on vascular function, cholesterol levels, glucose consumption. Randomized controlled data from the WHI study demonstrated no increased risk in first-time users of There is evidence that estrogen therapy may be cardiopro- HRT during the 5–7 years since initiation of treatment. The tective if started around the time of menopause and continued majority of subjects in the WHI study were overweight or long term (often referred to as the ‘window of opportunity’ obese, which may have affected their basal breast cancer risk.
concept). HRT reduces the risk of diabetes and, through Data from the WHI and the Nurses’ Health Study suggest improving insulin action in women with insulin resistance, it that long-term, estrogen-only administration for 7 and 15 has positive effects on other related risk factors for cardiovas- years, respectively, does not increase the risk of breast cancer cular disease such as the lipid profile and metabolic syndrome.
in North American women. Recent European observational In women less than 60 years old, recently menopausal and studies suggest that the risk may increase after 5 years.
without evidence of cardiovascular disease, the initiation of The concomitant dramatic decrease in HRT use and the HRT does not cause early harm and may reduce morbidity immediate reduction in breast cancer incidence post-WHI in and mortality from coronary heart disease. Continuation of some studies were presented as further proof of the HRT beyond the age of 60 years should be decided as a part of carcinogenic effect of estrogen; however, recent data indicate the overall risk–benefit analysis.
an increase in breast cancer incidence despite stabilization in Initiation of HRT in elderly women or those who are more the number of HRT users, suggesting that HRT may be a than 10 years postmenopause may be associated with promoter of an existing breast tumor rather than an initiator increased risk for coronary events, mainly in the first 2 years of use. It is therefore not recommended to initiate HRT There are insufficient data to evaluate the possible beyond the age of 60 years solely for the purpose of primary differences in the incidence of breast cancer using different prevention of coronary artery disease. Also, it is well accepted types, doses and routes of estrogen, natural progesterone and that initiation of HRT is not appropriate in the routine progestogens and androgen administration. Nevertheless, treatment of older women with coronary disease.
large European observational studies suggest that a differencein risk between estrogen-only and combined estrogen–progestogen therapy is seen with some categories of progesto- gens but not with natural progesterone derivatives.
Baseline mammographic density correlates with breast Systemic HRT and especially local estrogen can correct cancer risk. This does not necessarily apply to the increase estrogen deficiency changes in the urogenital tract and in mammographic density induced by HRT. The combined maintain vaginal health. HRT has benefits for connective estrogen–progestogen therapy-related increase in mammo- tissue, skin, joints and intervertebral disks. Combined CEE þ graphic density may impede the diagnostic interpretation of MPA for more than 4 years may reduce the risk of colon cancer. HRT initiated around the time of menopause or inyounger postmenopausal women is associated with a reducedrisk of Alzheimer’s disease.
Unopposed estrogen administration induces a dose-related stimulation of the endometrium. Women with a uterus should have progestogen supplementation to counteract this effect.
Continuous combined estrogen–progestogen regimens are Studies on the risks of postmenopausal hormone use have associated with a lower incidence of endometrial hyperplasia mainly focused on breast and endometrial cancer, venous and cancer than occurs in the normal population.
Updated IMS recommendations on postmenopausal hormone therapy Direct intrauterine delivery systems may have advantages.
individual circumstances, but research over the last decade has Regimens containing low-/ultra-low-dose estrogen and pro- helped to show that risks can be minimized and benefits gestogen cause less endometrial stimulation and less bleeding.
maximized with selection of the optimal regimen at the Long-cycle regimens and long-term use of monthly sequen- tial regimens do not provide optimal endometrial protection.
The safety of HRT largely depends on age. Healthy women SERMs other than tamoxifen do not stimulate the younger than 60 years should not be unduly concerned about endometrium and do not increase the incidence of endometrial the safety profile of HRT. New data and re-analyses of older spotting or bleeding compared to women not using any studies by women’s age show that, for most women, the potential benefits of HRT given for a clear indication aremany and the risks are few when initiated within a few yearsof menopause.
Thromboembolism and cardiovascular events The WHI and other studies strongly suggest that it is The HRT-related risk for serious venous thromboembolic significant in any increase in breast cancer risk rather events increases with age (although minimal in low-risk than the estrogen. Thus, it seems prudent to minimize women until age 60), and is also positively associated with progestogen use where safely possible and, in the near obesity and thrombophilia. Transdermal estrogen may avert future, progestogens may be replaced by SERMs that do the risk associated with oral HRT by avoiding first-pass not adversely affect the breast but also inhibit endometrial hepatic metabolism. The impact on the risk of a thromboem- bolic event may also be affected by the type of progestogen.
There is increasing evidence that non-oral routes of estrogen The risk of stroke is correlated with age, but stroke is a rare or tibolone have little or no increased risk of thromboembo- event before age 60. HRT may further increase that risk, lism and would be the regimens of choice in women with becoming significant after the age of 60. Low-dose transder- thromboembolic risk factors, if HRT was considered appro- mal preparations are not associated with increased risk for stroke. Safety data from studies of low-dose and ultra-low- There is mounting evidence from laboratory, animal, dose regimens of estrogen and progestogen are encouraging, observational studies and randomized controlled trials with fewer adverse events, but data from large prospective cardioprotection and neuroprotection if HRT is pre-scribed in midlife from near menopause in symptomaticwomen.
Women can have the option of HRT for as long as they derive symptomatic benefit and are aware of the risks for their The efficacy and safety of complementary alternative medicines regimen and personal circumstances. They can try without have not been demonstrated and further studies are required.
HRT every few years, but menopausal symptoms in some Selective serotonin reuptake inhibitors (SSRI), selective women can last for many years and should be treated with the noradrenaline reuptake inhibitors (SNRI) and gabapentin are effective in reducing vasomotor symptoms in short-term It is very unlikely that long-term, randomized, controlled studies. Their long-term safety needs further evaluation.
trials, like the WHI which finished prematurely, will ever be There are no medical or scientific reasons to recommend funded or be practically possible in the future. Therefore, unregistered ‘bioidentical hormones’. The measurement of clinicians in any field must treat or not treat on the balance of hormone levels in the saliva is not clinically useful. These the available data. Such data for the foreseeable future have ‘customized’ hormonal preparations have not been adequately and will come from short-term, randomized trials using tested in studies and their purity and risks are unknown.
surrogate endpoints for long-term morbidities (e.g. TheKronos Early Estrogen Prevention Study (KEEPS) and theEvaluation of Losartan In The Elderly (ELITE) study), or from long-term, non-randomized cohort studies (e.g. the Nurses’Health Study), or from systematic reviews of the quality There is urgent need for further research especially into the risks and benefits of lower doses, regimens and routes of The excessive conservatism engendered by the presenta- administration of HRT, and into late-life cognitive effects of tion to the media of the first results of the WHI in 2002 has disadvantaged nearly a decade of women who may haveunnecessarily suffered severe menopausal symptoms andwho may have missed the potential therapeutic window Postmenopausal HRT is not a single regimen given to a These IMS evidence-based recommendations are intended standard woman. The benefits and risks vary greatly in to encourage better care of all women in midlife.
Updated IMS recommendations on postmenopausal hormone therapy consider it to be significant; 50% of women complain ofstress incontinence, 11% urgency incontinence and 36% There is a wide variation in symptoms and signs of Better metabolic profile, balance, muscle strength, cogni- tion and quality of life are observed in physically active The loss of lubrication and hormonal changes may lead to persons. Heart events, stroke, fractures and breast and sexual dysfunction. Treatment of this condition improves colon cancers are significantly less frequent.
quality of life, not only for the woman but also for her The benefits of exercise far overweigh possible adverse consequences: the more, the better, but too much may Urogenital symptoms respond well to estrogens. Long- term treatment is often required as symptoms can recur on Optimal exercise prescription is at least 150 minutes of cessation of therapy. Systemic risks have not been moderate-intensity exercise per week. Two additional identified with local low-potency/low-dose estrogens.
weekly sessions of resistance exercise may provide further Use of systemic HRT does not seem to prevent urinary benefit. However, the recommended intensity of aerobic incontinence and is not preferable to low-dose local activity should take into account the older adult’s aerobic estrogens in the management of urogenital atrophy or recurrent lower urinary tract infections.
After lifestyle changes and bladder retraining, antimus-carinic drugs combined with local estrogens constitute first-line treatment in postmenopausal women with symp-toms suggestive of an overactive bladder.
Obesity (body mass index 430 kg/m2) affects over 20% of All women complaining of stress urinary incontinence the population in many parts of the world and is becoming will benefit from pelvic floor muscle training in the first an increasing problem in the lower socioeconomic sectors instance. Duloxetine may work synergistically with con- servative therapy. However, many women will ultimately Weight loss of only 5–10% is sufficient to improve many undergo surgery, and retropubic and transobturator tapes of the abnormalities associated with the insulin resistance There is currently no role for systemic estrogen therapy in The basic components of a healthy diet are: several women with pure stress urinary incontinence.
servings/day of fruits and vegetables, whole grain fibers,fish twice per week, and low total fat (but the use of oliveoil is recommended). Consumption of salt should be limited and the daily amount of alcohol should not exceed30 g for men and 20 g for women.
Lifestyle modifications include socializing, and being The public health approach to lifestyle promotion requires Osteoporosis is a systemic skeletal disease of diminished a multidisciplinary approach, starting from schools bone strength that results in fractures when falling from through to work places, involving the food and advertising one’s own body height. Bone strength is determined by a industry, as well as medical insurers and health authorities.
combination of bone density and microarchitectural A new paradigm in the doctor–patient relations is required, where the doctor becomes more of an advisor Postmenopausal osteoporosis can be caused by the failure and the patient has to take the responsibility for his/her to attain peak bone density or accelerated bone loss after Although skeletal health is a function of genetic predis-position, it can be modified by lifestyle factors such as diet, weight-bearing exercise and the avoidance of bone-toxicsubstances.
Symptoms such as vaginal dryness, soreness, dyspareunia, Hip fracture is responsible for a large proportion of the urinary frequency, nocturia and urgency are extremely financial burden of osteoporosis to health-care systems but common in postmenopausal women. The prevalence of other osteoporosis-related fractures, particularly vertebral incontinence in women increases with age. Overall, 25% fractures, cause considerable morbidity which can be long- of women report urinary incontinence of which 7% Updated IMS recommendations on postmenopausal hormone therapy some degree of fracture protection may remain aftercessation of HRT, the patient at high risk for fracture may The diagnosis of osteoporosis is based on BMD assessment be a candidate for additional therapy with proven bone- by dual X-ray absorptiometry (DXA), expressed as the T- score, or the presence of fragility fractures.
The continuation of HRT after the age of 60 years BMD is not a cost-effective population screening tool but for the sole purpose of the prevention of fractures is best applied on a selective basis, based on age and other should take into account the possible side-effects in the individual of the specific dose and method of The 10-year probability of fracture in an individual can be administration of HRT, compared to other proven estimated using a model that integrates various risk factors for fracture, such as the FRAX model developed through The initiation of HRT for the sole purpose of the the World Health Organization, which is available online prevention of fractures is not recommended after the age An appropriate assessment of prevalent fractures andsecondary causes of osteoporosis should precede anytherapeutic decisions.
Postmenopausal women need a dietary reference intake The goal of management in osteoporosis is the prevention (DRI) of 1000–1200 mg of elemental calcium.
of fracture. Choice of therapy should be based on a Calcium supplementation should be restricted to bridge balance of effectiveness, risk and cost.
the shortfall between dietary intake and the DRI and to Intervention thresholds for therapy can be based on 10- patients being treated for high fracture risk. Routine year fracture probability and will be country-specific.
dietary calcium supplementation cannot be justified in Alternatively, treatment can be given to all patients with a terms of efficacy and health economics. Calcium supple- fragility fracture or a T-score of 7 2.5 (osteoporosis), or mentation in excess of the DRI (total intake) may induce a T-score of 57 1.0 4 72.5 (osteopenia) and additional risk factors, as a large proportion of fractures occur in The DRI for vitamin D is 800–1000 IU in the post- Monitoring of therapy by serial DXA should be inter- As the major source of vitamin D is dependent on sunlight preted with caution and take into account the site exposure, the need for supplementation will vary.
monitored, time interval, drug-specific expectations and Measuring the blood 25-hydroxyvitamin D level may be the value of least significant change as calculated for the Vitamin D supplementation has been shown independently The monitoring of treatment by biochemical markers of to lower the risk of fracture and of falling in elderly bone turnover is presently not recommended in routine The cost-effectiveness of treatments to prevent osteoporoticfracture will be highest where they are used in women who have increased fracture risk. The relevant fracture riskthreshold will be specific to the individual health-care The bisphosphonates are potent inhibitors of bone resorption and decrease the rate of bone turnover, withproven efficacy in the prevention of vertebral and hipfractures.
A drug-free holiday may be considered after 3–5 yearsof bisphosphonate therapy in patients with a good HRT is effective in preventing the bone loss associated with the menopause or secondary amenorrhea.
HRT decreases the incidence of all osteoporosis-related Bisphosphonates have benefits in some cancers and may fractures, including vertebral and hip fractures, even in prevent bone metastases from breast cancer.
populations of women not at high risk of fracture.
Bisphosphonate-related osteonecrosis of the jaw is a rare HRT is one of the first-line choices of therapy in complication when dosages as recommended for fracture postmenopausal women in the age group 50–60 years prevention are used. An association has been suggested presenting with a substantial risk of fracture.
between atypical femur shaft fractures and oversuppres- The protective effect of HRT on BMD is lost after sion of bone turnover in patients exposed to bisphos- cessation of therapy at an unpredictable rate. Although phonates for longer than 3–5 years.
Updated IMS recommendations on postmenopausal hormone therapy Similar changes in connective tissue are observed at thearterial media layer.
The approved SERMs, raloxifene, lasofoxifene and baze- Intervertebral discs become thinner after the menopause doxifene, reduce the risk of vertebral fracture in post- and this may be prevented by estrogen therapy.
menopausal women with or without prevalent vertebralfractures. A combination of bazedoxifene and CEE hasbeen shown to preserve BMD.
Raloxifene is also indicated for reduction in risk ofinvasive breast cancer in postmenopausal women with The marked predominance of polyarticular osteoarthritis osteoporosis, but is associated with an increased risk of in women and, in particular, the marked increase of venous thromboembolism (VTE) similar to HRT.
osteoarthritis in women after the menopause suggest thatfemale sex steroids are important for cartilage homeostasis.
Timely initiation of estrogen/SERM treatment can effec- tively prevent both bone and cartilage loss accompanyingthe menopause, involving both direct and indirect Parathyroid hormone (PTH) produces a significant reduc- tion in the risk of vertebral and non-vertebral fracture bystimulation of bone formation. There is no indication thatcombining PTH with a bone resorption inhibitor has any additional benefit to giving either drug alone. Priortreatment with a bisphosphonate blunts the effect of Gender-specific characteristics of atherosclerosis PTH is given as a daily subcutaneous injection for amaximum of 18 months. Use is limited by high cost.
The clinical course of cardiovascular disease has gender-specific characteristics.
Menopause may be considered a risk factor for coronary artery disease (CAD) in women due to the potential effectsof ovarian failure on cardiovascular function, blood pressure and various metabolic parameters (glucose significantly reduces the risk of vertebral and non- Arterial hypertension, high triglyceride level and diabetes patients, irrespective of the presence of a fracture or are more important cardiovascular risk factors in women age. The mode of action of strontium ranelate involves stimulation of bone formation as well as inhibition of Preventative strategies should be focused in women on reducing blood pressure and controlling weight and glucosemetabolism. Women often have angina with non-obstructedcoronary arteries but, when they develop an infarct, their prognosis is significantly worse than that of men.
A human monoclonal antibody to the receptor activator ofnuclear factor-kappa B ligand (RANKL), at a dose of 60 Postmenopausal hormones and coronary artery mg subcutaneously 6-monthly, significantly reduces the risk of vertebral, non-vertebral and hip fractures. As withother biological therapies, denosumab may have adverse The majority of preclinical data and observational studies support the potential benefits of HRT in reducing risk ofCAD. Estrogen may induce beneficial effects on variousCAD metabolic risk factors. HRT was found to be associated with a lower risk of new-onset diabetes.
Randomized controlled trials (RCTs) reported mixed results.
RCTs exploring a possible association between cardiopro- Skin, the carotid artery and intervertebral discs tection and hormone use mainly included women withknown CAD or potentially having subclinical atherosclero- Estrogen protects connective tissue metabolism in the sis. Those RCTs had insufficient power to assess the effects of hormones on coronary risk in younger symptomatic After the menopause, there is loss of connective tissue in women initiating therapy around the onset of menopause.
the dermis of the skin which in some cases is reversed with In both the randomized and observational WHI hormonal trials, although the overall data were not significant for Updated IMS recommendations on postmenopausal hormone therapy benefit or harm, over the course of the studies there was a significant trend for decreasing coronary disease withtime.
Patient selection and timing of initiation may explain theseapparently conflicting results. Evidence from the major VTE is one of the major adverse events during use of oral randomized and observational trials points to the im- HRT and SERMs. The risk increases with estrogen dose, portance of age at initiation of hormone use. A coronary age and body mass index and is greater during the first benefit has been shown to be confined to women 510 Non-oral 17b-estradiol (but not non-oral ethinylestradiol), In younger women initiating HRT, all-cause mortality has by avoiding the hepatic first-pass effect, may be preferable been shown to be decreased, particularly due to a reduction in cardiovascular disease. Two ongoing pro- Population screening for thrombophilia is not indicated spective trials (KEEPS and ELITE), using carotid intima prior to HRT use. Selective screening may be indicated on media thickness and coronary calcium as endpoints, will the basis of personal and familial history.
provide data that may support this benefit.
Initiation of HRT has been related to more coronaryevents (termed ‘early harm’) during the first year of use.
However, this increased risk appears to be applicable onlyto elderly women with existing coronary disease and may Oral HRT induces both pro-inflammatory (liver biomar- be related to the estrogen dose at initiation. A difference in kers) and anti-inflammatory (vascular biomarkers) effects.
the coronary effects of added progestogen compared to Modification of inflammation in either direction can be estrogen alone has not been established.
good or bad for arterial disease depending upon the Based on currently available evidence, it is clear that HRT individual status of inflammation in the vascular wall, initiation has no place in the routine treatment of older potentially related to age and time after menopause.
women with coronary disease, and this includes data on The liver-derived pro-inflammatory effects of estrogen may be avoided by a non-oral route of administration of17b-estradiol.
There is limited evidence that different progestogens modulate liver and vascular inflammatory effects.
Although both CAD and stroke are arterial vasculardiseases, the effects of postmenopausal hormones on those very common conditions are not necessarily similar.
Hypertension increases the risk of stroke significantly.
Oral estrogen therapy and estrogen plus progestogentherapy increase risk of ischemic stroke by about one- During development and adulthood, the human brain is a third in relatively healthy postmenopausal women. In the target for estrogens and other gonadal steroid hormones.
WHI study, the excess risk was about one additional Estrogens influence neural function and neurological stroke per 1000 person-years. Observational findings from disease directly, through effects on neurons and glia, and the large Nurses’ Health Study are consistent. In another indirectly, through effects on oxidative stress, inflamma- large observational study, transdermal estradiol at a tion, the cerebral vasculature and the immune system.
dosage 50 mg did not increase the risk of stroke.
With menopause, the cessation of ovarian production of The excess absolute risk of HRT is expected to be lower estrogens and progesterone has the potential to influence among women below the age of 60 years, because stroke processes in the central nervous system relevant to incidence is lower in this younger age group. After neurological and psychiatric disorders. Within the brain, menopause, the relative risk of stroke does not vary however, some neurons remain capable of synthesizing significantly by age or temporal proximity to menopause.
Evidence from basic science studies reaffirms the neuronal Many women note cognitive and emotional symptoms at protective effects of estrogen in the setting of experimental times that are associated with changes in circulating levels of gonadal steroids. It has been more difficult, however, to Based on findings from a single, well-designed clinical trial demonstrate consistent cognitive and affective effects of of postmenopausal women with a history of ischemic stroke or transient ischemic attack, estrogen therapyshould not be prescribed for the secondary prevention of Data on progestogen use versus unopposed estrogen use For midlife women, observational evidence indicates no persisting effects of the natural menopause on memory or Updated IMS recommendations on postmenopausal hormone therapy other cognitive functions. During the menopausal transi- There is insufficient evidence to recommend HRT, either tion, however, some women experience transient prob- alone or as an adjunct, for treatment of depression.
lems, the magnitude of which is usually small.
Limited evidence from short-term clinical trials in midlifewomen suggests that HRT has no substantial cognitive For older women without cognitive impairment, there is Potential effects of HRT on the incidence or symptoms of convincing clinical trial evidence that HRT started in the Parkinson’s disease are largely unknown.
late postmenopause has no substantial impact on cognitive Based on evidence from a single, small clinical trial, combined HRT may increase seizure frequency in post- For surgically menopausal women, limited evidence from small clinical trials suggests that estrogen therapy could be Headache prevalence is lower after menopause than of short-term cognitive benefit when initiated at the time of before. Observational evidence suggests that current HRT is positively associated with headache.
The long-term cognitive consequences of HRT initiated Multiple sclerosis symptoms may be influenced by during the menopausal transition or early postmenopause hormonal status. It is not known whether HRT affects are unknown. There remains an urgent need for further multiple sclerosis symptoms or progression.
For women with dementia due to Alzheimer’s disease,limited clinical trial evidence indicates that HRT does The WHI study demonstrated that 7.1 years of treatment not improve dementia symptoms or slow disease with CEE only did not increase the risk of breast cancer diagnosis in hysterectomized women. The prospective Limited clinical trial evidence indicates that HRT cohort in the Nurses’ Health Study also reported that increases all-cause dementia risk when initiated in the unopposed estrogen did not increase the risk of breast late postmenopause. For women aged 65–79 years, the cancer diagnosis until after 15 years of estrogen exposure excess risk of dementia attributed to hormone use is (mostly CEE). Data about unopposed estradiol are about 1.2 per 1000 person-years for estrogen therapy conflicting, with some studies reporting an increased risk and 2.3 per 1000 person-years for estrogen plus of diagnosis with short-term duration, but with others progestogen therapy. In this age group, HRT risk may be higher for women with lower cognitive function at Data from the estrogen plus progestogen arm of the WHI showed an increase in breast cancer diagnosis at an Observational evidence implies that HRT used by younger average follow-up of 5.6 years, although, after adjustment women around the time of menopause is associated with for confounding variables, this was not statistically lower risk of Alzheimer’s disease. Findings from a recent significant. Women who had not used HRT prior to the observational study add new support to the concept of a study were not at a higher risk for breast cancer diagnosis therapeutic window, suggesting that using HRT in midlife for up to 7 years after initiation of therapy.
only is beneficial, with respect to dementia risk, whereas Micronized progesterone or dydrogesterone used in starting HRT in later life is harmful. In this study, taking association with oral or percutaneous estradiol may be HRT from midlife onward to older age carried a neutral associated with a better risk profile for breast cancer than synthetic progestogens for at least 5 years, but there arenot as yet adequately powered clinical studies.
The risk of breast cancer diagnosis decreases rapidly after cessation of HRT; by 5 years, the risk may not be greaterthan that in women without any history of exposure.
The prevalence of depressive symptoms is similar before Lifestyle factors associated with an increased risk of breast and after the menopause. However, depression risk may be cancer diagnosis include postmenopausal obesity, in- increased during the menopausal transition and the early creased alcohol intake and reduced physical activity.
Non-modifiable factors include family history, increased Limited clinical trial evidence suggests no effects of breast density and atypical ductal hyperplasia.
estrogen therapy on depression in the late postmenopause.
The increased risk of diagnosis observed with HRT may be Limited clinical trial evidence suggests that short-term partially decreased by selecting women with a lower estrogen therapy may benefit depression during the individual baseline risk and by providing education about preventive lifestyle measures. One caveat, however, is that Updated IMS recommendations on postmenopausal hormone therapy HRT does not appear to increase the risk of diagnosis in Several case–control and population studies suggest a overweight women whereas it does in women who are not significant increase in risk, but the effect of duration or overweight. This may be due to differences in circulating type of therapy varied among the studies. In one large- estrogen levels related to adiposity.
scale trial, the increased risk rapidly returned to normalwithin 2 years of cessation, consistent with a promoterrather than inducer effect.
In summary, long-term, estrogen-only therapy may be associated with a small attributable risk of ovarian cancerof 0.7 per 1000 women per 5 years of use, whilst either a Unopposed estrogen therapy is associated with a duration- significantly smaller, or no, increased risk is seen with and dose-related increase in risk of endometrial hyperpla- combined estrogen plus progestogen therapy.
This increased risk persists for many years after cessationof therapy.
Progestogen prevents the endometrial proliferation ofestrogen.
Lung cancer incidence in women continues to increase, Endometrial protection requires an adequate dose and mainly due to smoking, and lung cancer is the largest contributor to cancer mortality in women.
Long-term use of sequential combined HRT regimens may Large observational studies have reported a protective increase the risk of endometrial hyperplasia and cancer, effect of hormonal contraception and postmenopausal particularly the long-cycle regimens and where progesto- gens are used for less than 12 days per 30 days.
In the WHI RCT of estrogen-only therapy, there was no Continuous combined regimens are associated with a increase in the risk of non-small cell lung cancer.
lower risk of endometrial cancer than in the untreated In the WHI RCT of combined estrogen and progest- ogen therapy, there was an overall non-significant In the WHI and Million Women Study, there was no trend towards an increase in risk of non-small cell lung difference in risk of endometrial cancer with continuous An increased risk became significant only in women aged New lower-dose regimens cause less endometrial stimula- 60–69 years where the absolute attributable risk was 1.8 extra cases of lung cancer per 1000 women taking HRT Intrauterine delivery of progestogen is a logical route of administration and provides effective endometrial suppres- The risk of death from lung cancer was also higher for sion, but outpatient insertion may be problematic in HRT users and this increase was greatest amongst those Data from RCTs on the effect of tibolone on the In women aged 50–59 years, no increased risk of lung endometrium suggest a similar effect to continuous Tamoxifen has an estrogenic effect on the endometriumwhereas raloxifene and other modern SERMs have no Following treatment for endometrial cancer, the use of The majority of observational studies show a reduced risk HRT is not generally recommended, although there are of colorectal cancer amongst users of oral HRT.
Three meta-analyses have reported a reduced risk of Obesity increases the risk of developing endometrial colorectal cancer with HRT use with benefit persisting for 4 years after cessation of therapy. A typical effect wasrelative risk (RR) 0.80 (95% confidence interval (CI) 0.74–0.86) for ever-users and 0.66 (95% CI 0.59–0.74) for Results from the WHI randomized trial of estrogen-only therapy showed no effect of estrogen-only therapy on riskof colorectal cancer.
Premenopausal use of the combined oral contraceptive pill In the WHI RCT of estrogen and progestogen therapy, is associated with a reduced risk of developing ovarian colorectal cancer risk was reduced (RR 0.56; 95% CI 0.38–0.81). This effect was predominantly for local The WHI study is the only RCT to examine HRT and disease and, where spread had occurred, there was more ovarian cancer risk. In women receiving combined HRT, node involvement and a more advanced stage at diagnosis there was no significant increase in risk.
Updated IMS recommendations on postmenopausal hormone therapy HRT should not be used solely for the prevention of Validated tools (self-administered questionnaires/daily diaries and event logs/semi-structured interviews) may be There are no data for an effect of non-oral HRT on risk of used to diagnose sexual symptoms and to gain information on sexual constructs and relationships; sex steroid assaysare not generally helpful.
An accurate sexual history and a focused clinical evalua-tion may help clinicians in the management of sexual Long-term cohort studies have shown no increased risk of symptoms that are causing significant distress. Vaginal atrophy should be always diagnosed and appropriately In the WHI RCT, there was no increase in risk of cervical treated. Hormonal and non-hormonal treatments and/or psychosexual strategies should be individualized andtailored according to a woman’s history and current needs.
Gastric and esophageal cancers are predominantly diseases of men. The reason for this is unclear and no hormonalmechanism has been found.
Newly approved medications and late-stage products A nested case–control study showed a reduction instomach cancer for users of HRT (RR 0.48; 95% CI New low- and ultra-low-dose oral and transdermal pre- 0.29–0.79) but no effect on esophageal cancer.
parations appear to maintain benefits for symptom relief Oral HRT is known to affect gall bladder function and and osteoporosis while minimizing side-effects and risks.
observational studies have reported an increased incidence A number of new SERMs have been approved by of cholecystectomy amongst users of HRT.
regulatory agencies for indications related to osteoporosis The only report of gall bladder cancer and HRT comes and a SERM is being evaluated for the treatment of from a small case–control study which found an increased risk associated with HRT use and with duration of use Recent IMS recommendations on management of vaginal atrophy have highlighted the excellent benefit/risk ratio ofestrogenic and non-hormonal vaginal preparations. Anultra-low-dose vaginal tablet has recently received regula- tory approval. Clinical studies are ongoing into the possible use of vaginal dehydroepiandrosterone (DHEA)for atrophy and low libido.
Healthy status represents a major determinant of quality Studies of SSRI and SNRI products continue to try and of life, particularly in elderly people, but sexuality is an find a suitable non-hormonal treatment for hot flushes.
important factor at all ages as well.
A SERM/estrogen combination being developed to treat A complex interplay of biological, psychological and menopausal symptoms and for osteoporosis has completed socio-relational factors determines women’s sexual health.
This may negatively affect the entire sexual response cycle, A new injectable monoclonal antibody, targeting RANK inducing significant changes in desire, arousal, orgasm and ligand, has become available for the prevention of satisfaction at menopause and beyond.
fractures in postmenopausal women with osteoporosis Both age and declining sex hormones have detrimental effects on sexual functioning, with a significant increase in Transdermal testosterone has been approved in a number vaginal dryness/dyspareunia and a significant decrease in of countries for the management of hypoactive sexual desire disorder in surgically menopausal women on The partner’s general and sexual health and the quality of concomitant estrogen. Although data exist for use in the relationship may significantly contribute to the natural menopause and without concomitant estrogen, relevance of sexual symptoms in postmenopausal women.
these indications have not yet been approved by the Reduced libido is the most common sexual complaint regulatory authorities pending further data.
experienced by women and the proportion increases withage. However, there are age-related changes in sexuallyrelated personal distress, which are especially evident in surgically menopausal women. These women are atincreased risk for hypoactive sexual desire disorder.
Non-oral estradiol and progestogens avoid the first-pass Women may not be willing to initiate a conversation on metabolism and therefore have the potential for less sexual interest, behavior and activity themselves, but they stimulation of the liver proteins and a neutral metabolic usually appreciate being questioned by doctors.
Updated IMS recommendations on postmenopausal hormone therapy The risk of venous thromboembolism is less with There is little evidence that dietary modifications or transdermal than with oral estradiol.
exercise improve hot flushes but they may improve mood First uterine pass of vaginal delivery of progestogens leads and quality of life. Regular exercise, weight reduction, and to adequate local concentrations and good endometrial avoiding triggers to hot flushes (such as caffeine or direct protection, but with very low systemic progestogen levels.
heat) may help to minimize hot flushes or their impact.
The combination of non-oral administration of estradiol Randomized trials of acupuncture have not consistently and direct intrauterine delivery of progestogen or vaginal shown a beneficial effect in reducing vasomotor symptoms.
ring delivery of progesterone may improve compliance.
Long-term, good-quality studies are still needed.
Recent observational studies have indicated that the Complementary therapies for vasomotor symptoms transdermal administration of postmenopausal estrogenis not associated with an increased risk of cardiovascular High-quality studies to date have not consistently sup- complications, specifically stroke and venous thrombosis.
ported the efficacy of complementary or over-the-countertherapies in reducing severity or frequency of hot flushes ornight sweats.
Black cohosh and soy products are not superior to placeboin the treatment of hot flushes.
Postmenopausal women with intact ovaries usually do notsuffer from androgen deficiency and do not require routineandrogen replacement.
So-called ‘bioidentical’ or ‘natural’ hormones The correlation between women’s sexual function andpsychosexual variables is complex. Therefore, androgen Such labelling and advertising has no sound scientific basis deficiency can be confounded with other causes of sexual to delineate them from many current forms of registered dysfunction such as relationship distress, emotional Estradiol, estrone or estriol, whether pharmaceutically There is no correlation between serum levels or total produced or compounded as a ‘bioidentical’ product, are androgen activity and sexual dysfunction. Oral methyltes- synthesized usually from the vegetable yam and are tosterone, testosterone undecanoate and transdermal testosterone replacement in oophorectomized as well as Other so-called ‘natural’ but synthesized human hormones in healthy postmenopausal women, with and without that can be mixed into untested ‘bioidentical’ concoctions concomitant use of estrogens, have shown a beneficial can be progesterone, testosterone, DHEA, thyroxine, effect in several large RCTs. The administration of a transdermal patch delivering 300 mg of testosterone per These hormones are usually administered in troches day resulted in a significant increase in the number of self- (buccal lozenges) or transdermal creams, compounded by reported sexually satisfying events per month as well as local chemists on the prescription of medical practitioners, desire, arousal, responsiveness and orgasm, which were in combinations and doses that have never been tested in impaired at baseline in the participating cohorts.
Oral DHEA does not significantly improve sexual function There are inadequate quality data to show the long-term except in women suffering from adrenal insufficiency.
safety or efficacy of any of these products.
There are no data on breast and endometrial safety with Endometrial cancer has been associated with estrogen- containing bioidentical hormones. If used in the bioiden- The role of vaginal DHEA administration for improv- tical mixture at all, the progesterone used may not inhibit ing sexual function in postmenopausal women is estrogen-induced endometrial hyperplasia.
Hormonal assay of saliva is sometimes claimed as a way ofassessing hormonal need and of titrating the compounded ‘natural’ hormones. There are no data to show that salivary hormonal assay can reliably achieve these aims.
Bioidentical hormones are extensively marketed directto the public on the internet and in other media, often Non-pharmacological and lifestyle interventions with unproven and unlikely claims such as they have noside-effects, are safe, will help you lose weight and are High-quality data from studies of non-pharmacological and lifestyle interventions for vasomotor symptoms have Locally compounded ‘bioidentical’ hormones are not subject to the scrutiny of pharmaceutical regulatory bodies Meditation, relaxation, controlled breathing and cognitive in many countries and the manufacturers can avoid having behavior therapy show promise in managing hot flushes, to test their products for quality control, safety and but adequately powered randomized trials are still needed.
Updated IMS recommendations on postmenopausal hormone therapy These unproven products and the associated inaccurate with tamoxifen, venlafaxine, desvenlafaxine, citalopram saliva tests are usually promoted for commercial gain and are much more expensive than proven registered pharma- Sudden cessation of a SNRI or SSRI may cause withdrawal symptoms and they should be discontinued gradually by All main-stream scientific, clinical and regulatory bodies in women’s health advise against the prescription and use ofthese hormones.
The prescriber is at risk of future medicolegal claims.
Vaginal atrophy becomes clinically apparent 4–5 years Pharmacological agents for vasomotor symptoms after the menopause and objective changes as well assubjective complaints are present in 25–50% of all The mechanisms underlying vasomotor symptoms are still It is essential that health-care attendants routinely engage in There have been very few head-to-head studies of non- open and sensitive discussion with postmenopausal women about their urogenital health to ensure that symptomatic Currently, the only preparation which has demonstrated atrophy is detected early and managed appropriately.
equivalent efficacy to estrogen is gabapentin. Gabapentin Treatment should be started early and before irrevocable (300 mg three times per day) was equivalent to low-dose estrogen (0.5 mg CEE or a 25 mg estradiol patch) for Treatment needs to be continued to maintain the benefits.
All local estrogen preparations are effective and patient No other agents have been directly compared with preference will usually determine the treatment used.
estrogen for the reduction of vasomotor symptoms.
All currently available topical estrogens are absorbed, the Venlafaxine, desvenlafaxine, fluoxetine, paroxetine and extent depending on dose and formulation.
citalopram have all been shown in RCTs to reduce Additional progestogen is not indicated when appropriate vasomotor symptoms. A recent head-to-head study found low-dose, local estrogen is used although long-term data that venlafaxine (37.5 mg per day increasing to 75 mg controlled release) was equally effective but better If estrogen is ineffective or undesired, vaginal lubricants tolerated than gabapentin (300 mg once per day increasing and moisturizers can relieve symptoms due to dryness.
to 300 mg three times per day) in breast cancer patients.
There are few data on the use of vaginal estrogens in Both products reduced the frequency and severity of hot women with gynecological hormone-responsive cancers so flushes (by 66%) but side-effects were greater with they should be used with discretion.
Use of local estrogen in women on tamoxifen or aromatase In breast cancer patients, the SNRI venlafaxine was inhibitors needs careful counselling and discussion with equally as effective as clonidine in reducing vasomotor symptoms but clonidine was better tolerated. Efficacy upto 12 weeks has been demonstrated for these agents.
In general, these non-hormonal agents reduce hot flushes by 50–60%. This level of reduction appears to be acceptable to many women who wish to avoid hormones.
For those with mild/moderate hot flushes, it is reasonable There is a hierarchy of scientific evidence which should be to start with clonidine treatment. For moderate to severe taken into account when drawing conclusions from any hot flushes, or when clonidine fails or is not available, scientific investigation. In general (from the highest consider venlafaxine or gabapentin. These agents may standard or level of evidence to the lowest), the standards act by different mechanisms, so, if one fails or is not of evidence are: meta-analyses of RCTs, RCTs, observa- well tolerated, the other can be tried. If these are not tional trials, and, lastly, expert opinion. However, both effective, consider paroxetine, but avoid in those on RCTs and observational trials must be interpreted with caution, particularly in reference to HRT.
A key consideration in breast cancer patients using non- Observational trials (e.g. the Nurses’ Health Study) are hormonal agents is concomitant tamoxifen use. Agents primarily used for hypothesis development and not to which inhibit the enzyme CY2D6 can affect tamoxifen prove cause and effect. Inherent biases in observational metabolism and may reduce the efficacy of tamoxifen in studies of HRT typically include: selection bias – healthier preventing new breast cancers or their recurrence. Agents women prescribed HRT; prevention bias – monitoring and which interact with the cytochrome P450 system include treatment more intensive in women prescribed HRT; paroxetine, fluoxetine and buproprion and these should compliance bias – patients with greater adherence (even not be used in conjunction with tamoxifen for the to placebo) have better outcomes; survivor bias – treatment of depression or vasomotor symptoms. For use HRT may be stopped due to illness; prevalence-incidence Updated IMS recommendations on postmenopausal hormone therapy bias – early adverse effects of HRT not observed if user coverage sometimes includes totally wrong reports, or dies before becoming part of cohort.
superficial and uncritical evaluations taken from the RCTs (e.g. WHI) are primarily used for hypothesis testing, abstracts of selected journals, without reference to the to prove or disprove cause and effect. They can be entire article or the author’s own discussion of the findings.
downgraded in their level of evidence due to mitigating Media coverage has done a good job of telling women factors such as: a large dropout rate, lack of adequate what to be concerned about if they are using HRT, but a representation of the applicable group of women, and the poor job of providing the information women need to modifying influence from prior hormone use, for example.
determine whether the latest findings apply to them.
The WHI was recently downgraded to a level of evidence There is a general distrust of large organizations and particularly of research done by the pharmaceutical The World Health Organization (WHO) Council for industry, despite its conformance to regulatory agencies, International Organizations of Medical Sciences (CIOMS) both in the US (FDA) and in other countries of the classifies the frequency of drug reactions, which would world (e.g. EMEA). This distrust leads to denial of the include the impact of HRT or estrogen therapy, as: findings if they do not agree with one’s own precon-ceived expectations. Even when the findings are un- expectedly positive, they are often assumed to be Common (frequent) 41/100 and 51/10 (41% and 510%) spurious or falsified in the name of profit.
Uncommon (infrequent) 41/1000 and 51/100 (40.1% Rare 41/10 000 and 51/1000 (0.01% and 50.1%) We thank Professor M. Hickey, Australia for her assistance However, these frequencies do not necessarily indicate with the sections on Non-pharmacological and lifestyle clinical relevance. Rare findings in very large RCTs and interventions, Complementary therapies for vasomotor symp- observational trials may be statistically significant because toms, and Pharmacological agents for vasomotor symptoms.
of the large sample size, but may be clinically irrelevant The following attended the Workshop in 2007 and in their application to a particular patient in the clinical contributed to the previous Recommendations: P. Albertazzi, setting. Failure to provide a clinical context is often a UK; D. Barlow, UK; E. Berry, Israel; M. H. Birkha¨user, significant problem in relation to study outcomes. This is Switzerland; W. Bo¨cker, Germany; M. Brincat, Malta; H.
one of the reasons for providing the absolute risks noted Burger, Australia; C. Christiansen, Denmark; T. J. de Villiers, above. In one study, for example, electric blanket use was South Africa; J-M. Foidart, Belgium; M. Gambacciani, Italy; associated with a relative risk equal to 5 for breast cancer.
A. R. Genazzani, Italy; V. W. Henderson, USA; K-E. Huang,Taiwan; J. Huber, Austria; C. Kluft, Netherlands; K.
Limpaphayom, Thailand; R. A. Lobo, USA; M. A. Lumsden, UK; A. H. MacLennan, Australia; A. MacLennan, Australia; D. Murphy, UK; F. Naftolin, USA; R. E. Nappi, Italy; S.
Palacios, Spain; N. Panay, UK; J. H. Pickar, USA; A. Pines, The mass media has a tremendous influence over what Israel; R. Rizzoli, Switzerland; G. Rosano, Italy; J. Russo, the public ‘knows’ about HRT. Media-driven percep- USA; G. Samsioe, Sweden; H. P. G. Schneider, Germany; S.
tions also influence clinical decision-making, particu- Shapiro, South Africa; R. Sitruk-Ware, USA; S. Skouby, larly by those less familiar with the primary data being Denmark; J. C. Stevenson, UK; D. W. Sturdee, UK.
reported by the media. Each new news report is treated Delegates of menopause societies from the following as if it were the most important and of the highest countries participated in the discussions on the Recommen- quality, often to the exclusion of the bulk of scientific dations: Argentina, Australia, Austria, Belgium, Bolivia, evidence. For example, the initial results of the WHI Brazil, Bulgaria, Chile, Costa Rica, Croatia, Denmark, estrogen plus progestogen arm received enormous Dominican Republic, Ecuador, Egypt, El Salvador, Finland, media coverage – more than 400 newspaper stories France, Germany, Greece, Guatemala, Hungary, Hong Kong, and 2500 television-radio stories in the US alone, yet India, Indonesia, Israel, Italy, Japan, Lithuania, Malaysia, subsequent WHI reports have received much less press Mexico, Netherlands, Nicaragua, Norway, Panama, Peru, coverage, leading to the impression that surgically Philippines, Romania, Russia, Serbia, Singapore, Slovenia, menopausal women on estrogen without progestogen South Africa, South Korea, Spain, Sweden, Switzerland, have similar risks as noted in the initial reports (WHI Taiwan, Thailand, Turkey, United Kingdom, United States of The press tends to focus on negative news (e.g. breastcancer) to the exclusion of any positive findings such as all- cause mortality, cardiovascular disease prevention in report no associations or financial relationships with any younger women, or fracture reduction. Also, media pharmaceutical company, other than consultative agreements, Updated IMS recommendations on postmenopausal hormone therapy honoraria for lecturing at scientific meetings, and research support. Details of all disclosures have been updated and are dations have been supported entirely from the funds of the Kenfield SA, Stampfer MJ, Rosner BA, Colditz GA. Smoking and smoking cessation in relation to mortality in women. JAMA Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progesterone in healthy post- Eliassen AH, Hankinson SE, Rosner B, et al. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiolo- gical evidence on physical activity and cancer prevention. Eur J Anderson GL, Judd HL, Kaunitz AM, et al. for the Women’s Health Initiative Investigators. Effects of estrogen plus progestin on Baer HJ, Glynn RJ, Hu FB, et al. Risk factors for mortality in the gynecologic cancers and associated diagnostic procedures. JAMA Nurses’ Health Study: a competing risks analysis. Am J Epidemiol Harman SM, Brinton EA, Cedars M, Lobo R, et al. The Kronos Early Estrogen Prevention Study. An ongoing trial of the effects of earlyinitiation of HRT on coronary artery disease. Climacteric Aging, menopause, cardiovascular disease and HRT. Proceedings of Cardozo LD, Bachmann G, McClish D, et al. Meta-analysis of the 8th IMS workshop. Climacteric 2009;12(Suppl 1) estrogen therapy in the management of urogenital atrophy Center for Media and Public Affairs; commissioned by the Hormone in postmenopausal women: Second report of the Hormones Foundation. Analysis of media coverage of hormone therapy for and Urogenital Therapy Committee. Obstet Gynecol 1998;92: menopause management: 2002 through 2007. Cardozo L, Lose G, McClish D, et al. A systematic review of estrogens Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities for recurrent urinary tract infections: Third report of the recorded in the Women’s International Study of long Duration Hormones and Urogenital Therapy Committee. Int Urogynecol J Oestrogen after Menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women.
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eadaches are bad enough, but, oh, those mi-aged cheese, chocolate, organ meats (kidney, liver), graines! Here are some thoughts for those of sour cream, soy sauce, vinegar (relish, salad dress-you who are experiencing this terrible pain. ings, sauces, catsup), yogurt and yeast extracts. Oth-ers contain Nitrites found in processed meats such Symptoms as bacon, bologna, canned ham, cor

Microsoft word - zygophyllaceae_definitivo2008_10_17.doc

5. Tribulus L.* [Tríbulus, -i m. -- gr. tríbolos, -ou m.; lat. tribolus(tribulus), -i m. = entre otras cosas, el nombre de unas cuantas plantas con espinas (en hojas, frutos, etc.) u, otras veces, con tres folíolos, como el abrojo (Tribulus terrestris L., Zygophyllaceae) --gr. tríbolos chersaîos; lat. tribulus agrestis o tribulus siccus --, el abrojo o castaña de agua (Trapa

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