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In the second phase of the workshop, each of the relevant outcomes were discussed and ways to improve the collaboration between the various disciplines were considered. A framework for these deliberations were provided by a consensus document which formed the results of a consensus meeting held by the French menopause society and 10-20 other national societies in Athens in May 2003. On the basis of this document, the workshop participants discussed the various outcomes (breast cancer, cardiovascular disease, bones and joints, colon cancer and mental aspects), which had been the topics of the Kloster Andechs Workshop. For each of the points discussed, the wording of the conclusions reached at the Athens consensus meeting prefaces the summary of the ensuing Kloster Andechs discussions. [ABSTRACT FROM AUTHOR]

After many discussions, the workshop participants reached a number of conclusions regarding the benefits and risks of hormone replacement therapy based on the evidence available. The first conclusions related to the validity of the evidence as supplied by the new studies, namely the WHI and Million Woman studies. The main results found by these and other studies as they apply to breast cancer are summarized in Table 1 for reference, and the summary estimates of meta-analyses are shown in Table 2. [ABSTRACT FROM AUTHOR]

Mr. Heilmann discussed the perception and the acceptance of risk in the population. This is not determined by facts but by hopes and expectations. Risk to the individual is a subjective estimation. The question which concerns the pharmaceutical manufacturer in particular is how to measure and communicate risk. There is currently no measure which can adequately communicate risks associated with drug uses to the general population. Usually there is victim-oriented media reporting without reference to the total number of people who take the drug, so that case numbers may sound huge. The communication of relative risk is a problem if the baseline risk is not also communicated. A safety scale similar to the Richter scale of measuring earthquakes according to Heilmann and Urquhart is shown. [ABSTRACT FROM AUTHOR]

Professor Shapiro expressed concern with the general direction of epidemiology. Whereas the previous position was that we are unable to interpret limited data, this emphasis has shifted. In particular, the randomized controlled trial (RCT) now is unassailable in the US. Shapiro identified the current issues as being (1) a loss of scepticism in the field, (2) the illusion of accuracy and validity fostered by large databases and their seduction into believing statistical significance, and (3) an over-interpretation of RCTs. Examples of significant errors in epidemiology include spurious associations found for reserpine and breast cancer, calcium channel blocker and cancers in a follow-up study, and fertility drugs and ovarian cancers shown in meta-analysis. The lesson is that one must always be sceptical. The duty of epidemiologists engaged in research is to assume the null hypothesis. They should accept this until the null can be rejected with confidence. Related to the loss of scepticism are the following. Small relative risks are often uninterpretable. If there are fragile data based on small numbers then the data need to be almost free of error or biases. If not, they can change the estimate in such a way as to make the result uninterpretable. Black box statistics might produce nontransparent results. Particularly the meta-analysis of data is often misleading. When causal inference is made in epidemiology, there is a hierarchy of study types as to the level of proof they supply. From highest to lowest, these are RCT, cohorts, case-control, cross-sectional, ecological and descriptive studies. Case-control and cohort studies are simply alternate methods of sampling the population with neither method in principle superior to the other. RCTs are still considered to provide the highest level of proof, but in epidemiology, they cease to be RCTs. RCTs covering a time of 3-7 years become epidemiological follow-up studies, similar to regular cohort approaches. An example of how a study designed to be a randomized trial turns into an observational study is the WHI study, which explored oestrogen plus progestin (EP) vs a placebo. The clinical prediction is that women will experience some specific symptoms during menopause. This is confirmed by the fact that the proportion that unblinded due to the occurrence of vaginal bleeding in the EP group was 44.4% and 6.2% in placebo. The relative risk (RR) of this is 6.5, the risk difference is 37.6%. In addition, there is the potential for detection bias, as women are going to examine their breast more carefully because they are on HRT, if they are unblinded. The cumulative proportion of discontinuation in the HRT group was 42%, in placebo 38%. There is a large pool of women with otherwise silent breast cancer. The annual incidence of breast cancer was 3.8/1,000 in WHI for EP, 3.0/1,000 for placebo, the hazard ratio (HR) was 1.26 (1.00-1.59; p > 0.05). The corresponding risk difference is 0.8/1,000 per year. Other outcomes show similarly small differences, with an excess of 0.07% for CHD, 0.08% for stroke, pulmonary embolism 0.08%, i.e. each with an approximate risk difference of 1/1,000. All these are enormously susceptible to bias, particularly pulmonary embolism. The Million Women Study showed a risk estimate of 1.3 (1.22-1.38) for oestrogen and 2.0 for combined therapy; for tibolone it was 1.44. When seen on the population scale, this amounts to an incidence among EP users of 5.6/1,000 per year; the excess is 2.5/1000 per year. It cannot be said from these data whether HRT does or does not increase the risk because epidemiology is too crude a science. [ABSTRACT FROM AUTHOR]

The objective of the Million Women Study was to asses the risk of breast cancer in users after different regimes of HRT. This was a prospective cohort study on women invited for breast cancer screening. Of those invited, 75% accepted, and 71% (53% overall) of those who accepted actually participated. They ranged in age from 50 to 64 years, recruitment was between 1996 and 2001, with a follow-up from 2.6 to 4.1 years. Mortality was followed up 1- 2 years longer. Information was gathered on history of hormone use. Women were allocated to the hormone group they had when they entered the study. The HRT which was evaluated was the latest one used, irrespective of whether this was the one used longest. Ever use, current use, length of use, age at first use, time since last use and type of hormone used most recently entered the analysis. The average age of women in the study was 55.9 years. There were 9,364 cases of breast cancer and 637 deaths from breast cancer. The risk ratio (RR) for current use of HRT against non-use was 1.66, for past use it was 1.01, and the risk disappeared within one year after cessation. Combined HRT showed a RR estimate of 2. The RR of death of breast cancer is 1.22. Oestrogen-only therapy showed no difference by dose, implants showed an RR of 1.6. The specific estimates on oestrogen types are given. For example, levonorgestrel showed a risk ratio of 1.9 for less than 5 years of use, 2.23 for more than 5 years, but no consistent pattern for differences in risk for sequential and continuous users. Ex-users had no excess risk. The absolute life-time risk of BC is about 10%, and it is 9.7% for never users. The etiological fraction of HRT for BC is approximately 4%. The important messages of this study are that the risk of breast cancer associated with HRT disappears within a year after cessation, and that HRT in general has a modest influence compared with other lifestyle habits. [ABSTRACT FROM AUTHOR]

Professor Windler described the population data on cardiovascular disease (CVD) in women and the results of the CORA study conducted in Hamburg, Germany. CVD and stroke constitute much greater population risks than cancer. The determinant of obesity and subsequent myocardial infarction (MI) in older women appears to be the weight gain which occurs between age 20 and 40. Metabolic syndrome is characterized by insulin resistance (not necessarily diabetes). In Germany, only half of type II diabetics are actually diagnosed, whereas insulin resistance is not detected at all. Smoking is not an independent risk factor for CVD, according to the CORA study. It is not the smoking, but smoking in combination with some other factor, primarily hypertension. Although two-thirds of Japanese smoke, their MI rates are very low. The WHI results show that HRT may counteract insulin resistance. In the HERS study, no increased or decreased risk of CVD was found for HRT. An increase in risk was found in the first few months, however, which has also been found in the Nurse's Health study (Grodstein 2000). It should be noted that the WHI included only asymptomatic women and therefore does not reflect the treatment population. In HERS, women who receive HRT and have high lipids and then receive a statin had no increase in CVD risk compared with those who did not receive statins. In the CORA study, HRT users in general have a healthier lifestyle than non-users. The small group of HRT users who acquire disease in CORA have a high risk profile. Arteriosclerotic cardiovascular disease has become the major cause of death for women. Despite the increase in risk at the time of menopause, oestrogen deficit is certainly not the only responsible factor, since during the same period the incidence of classical risk factors increases dramatically. Typically women gain most of their weight even before menopause and develop a metabolic syndrome as a common risk profile, with the important elements of prevention being healthy nutrition and physical activity. The effects of oestrogens are so diverse that results of studies on elderly women or patients with coronary artery disease cannot be generalized. Unfortunately, intervention studies on the effects of hormone replacement therapy in women at the critical age of perimenopause are lacking. However, the data of the Women's Health Initiative (WHI) do not point to an increased risk in this phase. The Heart and Estrogen/Progestin Replacement Study (HERS) supports the notion that women even with coronary artery disease are not at increased risk given adequate medical treatment. Still, before starting hormone replacement therapy a predisposition for thromboembolic events should be excluded and blood pressure, blood sugar and lipids should be checked and treatment initiated, if necessary. As part of comprehensive medical care, low-dose oestrogens remain an effective and safe mainstay for the relief of perimenopausal symptoms. [ABSTRACT FROM AUTHOR]

Professor Schneider discussed the current status of the diagnosis of postmenopausal symptoms and the indication for HRT. The diagnostics for postmenopausal women include the subjective assessment of vasomotor changes (hot flushes), psychology (mood changes), and alterations of the target tissues (urinary symptoms, vaginal discharge). It is known that oestrogen modulates serotonin synthesis and the CNS thermoregulatory set-point. One diagnostic measure is the evaluation of core temperature and the evaluation of the tendency towards thermal response due to vasodilation. There may be some destabilization due to loss of serotonin receptors. The principal indication for HRT is for vasomotor relief in menopause. The time of treatment until an effect is seen is usually 2-4 weeks, but there is a wide range of responses, and placebo effects are known. Other therapies are not as effective as HRT. Even 18 years after menopause, 16% of women exhibit considerable vasomotor and other complaints, so that the duration of HRT use needs to be individually gauged. HRT has been shown to reduce sleep disorders, such as insomnia induced by decreased REM sleep and sleep apnea. There is no specific relation of natural menopause to mood disorders, although a subgroup of women may be subject to mood symptoms. A further issue is the differentiation between oestrogen deficiency and female androgen insufficiency. Dyspareunia is influenced both by androgen and oestrogen deficiency. Local application of low-dose oestradiol may help here. For vulval atrophy, local androgens are appropriate, atrophic vaginitis and urinary symptoms are treated with oestrogens. Transdermal testosterone treatment increases sexual activity. In treating dryness and atrophy, HRT up-regulates the skin collagen content, therefore re-establishing skin thickness and vascularity. Weight changes are an issue, because usually 10%-15% of body weight is gained during menopause, and it is one of the reasons that women will not accept HRT. Bone mass depends on exercise load and calcium intake. Osteoblasts respond both to androgen and oestrogen. Exercise, with its potential to increase androgen activity, leads to an increase of bone mass. Bone mass determinations depend very much on the bone site on which this measurement is done. Bone density is associated with oestrogen levels. Substitute oestrogen also has effects on bone density, but there are about 15% women who do not respond regardless of dose. Calcium was found to be ineffective in the early postmenopause period, but shows some effect in later menopause. The combination of oestrogen and parathyroid hormone (PTH) combines antiresorptive and bone-forming drugs. PTH thickens trabeculae and bridges the gaps in bone, i.e. it is bone-forming. The alternative treatments include bisphosphonates. Different treatment effects for tabecular and cancellous bone (i.e. hip) have been shown for the various drugs used against osteoporosis. [ABSTRACT FROM AUTHOR]

Professor Böcker stated that while little is known about regeneration, stem cells, or proliferative diseases, it is established that the breast consists in the main of two types of epithelium, glandular and myoepithelial, each deriving from progenitor cells. The current paradigm for breast cancer posits the formation of an intraductal lesion which then proliferates, but this has not been proven. The epithelium in the breast is very immature and contains many progenitor cells. One progenitor cell can differentiate either into myoepithelial or into glandular cell lines. The mature glandular cell has oestrogen receptors, the lactating glandular cells lose oestrogen receptor capability. Nothing is known about how involution after weaning actually occurs. Duct hyperplasia due to proliferation of immature cells of the glandular lineage is considered to be the first stage leading to breast cancer. All benign lesions are progenitor cell lesions. In breast cancer, ductal carcinoma shows specific a immuno-phenotype compared with the usual ductal hyperplasia. Breast cancer is not derived from progenitor cells, but usually evolves from glandular differentiated cells. These are the cells which are regulated by oestrogens and which have the highest proliferative activity. [ABSTRACT FROM AUTHOR]

The question of a potential relationship between HRT and the occurrence of ovarian carcinoma is addressed. Because 50%-60% of nonmucinous carcinomas have oestrogen receptors, in principle a relationship is possible. A recent publication by Risch (2002) reviewed 20 studies which were completely different in size, outcome, and exposure, so that no real comparison is possible. Risch found that "for every study showing a positive association, there are 3 which show no association." Five of the studies reviewed showed a slightly increased risk associated with HRT. The question here is whether this is due to induction or due to a previously undiscovered ovarian carcinoma which becomes apparent when on hormone therapy. All studies reviewed have shown a reduced risk of colon cancer associated with HRT treatment. These findings are plausible from a biopathological perspective, because while normal colon mucosa contains oestrogen receptors, these are methylated, meaning that they are inactive. Oestrogen stabilizes this methylation; therefore a risk reduction can be assumed. Professor Dietel concluded that on the basis of this evidence, HRT can be given to patients with colon cancer. [ABSTRACT FROM AUTHOR]

Professor Horn discussed the pathogenesis of different histological types of endometrial carcinoma. The known risk factors for endometrial cancer are age, obesity, late first birth, nulliparity, alcohol use, oral contraceptive (OC) use, and HRT use. The WHI study on endometrial carcinoma had 22 women on HRT (0.05%) and 25 women on placebo (0.06%). There was no statistically significant difference. Professor Horn described three primary types of endometrial carcinoma, namely a perimenopausal, endometrial cell type with hyperoestrogenism (type 1), a postmenopausal, deep invasion, clear-cell, serous-papillary type (type 2), and a tamoxifen-induced type (type 3). The latter comprises a polyp induced under treatment with tamoxifen which might turn into cancer, particularly among obese women. The survival rate for type 1 endometrial cancer (70%-80%) is better than for type 2, which has a 5-year survival rate of 60%. Only the atypical form of endometrial hyperplasia presents a true cancer risk. Hyperestrogenism leads to hyperplasia and therefore may lead to atypical forms which may cause endometrioid adenocarcinoma. It appears that postmenopausal women with unopposed HRT have two to three times the risk of endometrial adenocarcinoma, and that cancer risk is reduced with the use of sequential HRT. There is a down-regulation of oestrogen receptors (ER) and progesterone receptors (PR) with reduced hormone sensitivity. The progesterone application reduces oestrogen stimulation and therefore decreases cancer risk. The familial (endometrioid) endometrium carcinomas show fivefold increased risk. The cause of type 2 carcinoma is unknown. Apparently polyps are induced, which in rare cases develop into serous-papillary or clear-cell carcinomas. This affects primarily older women. [ABSTRACT FROM AUTHOR]

Epidemiology is a discipline which focuses on the observation of conditions and disease risks in human populations. It should not be confused with clinical trials, which, although they are a subset of epidemiological and biostatistical technique, are experimental, not observational. In the first presentation on epidemiology, Professor Heinemann showed that breast cancer constitutes 26% of all cancers in women (17.9% of all deaths) and that the incidence rates (i.e. the annual rate of new occurrences) for breast cancer in industrialized nations are high: 115.6 per 100,000 in the US and 100 per 100,000 in France, for example. Breast, ovarian and endometrial cancer are highest in industrialized nations. This raises the question of whether these differences are based on shared causality or on shared biases and confounding. The ratio from lowest to highest incidence in various countries is 1:20 for breast and endometrial cancer. Migration studies show an inversion of risk. The maximum effect of known risk factors is 1:1.5 or 1:2 (i.e. HRT, etc.). Breast cancer is associated with obesity, alcohol intake, low or late parity, and genetic inheritance. The incidence of breast cancer is high. However, the case fatality (the proportion of deaths among individuals who have the condition in question) for colon and ovarian cancer is much higher than that for breast cancer and for uterine corpus cancer. Breast cancer has high incidence in lower age groups, whereas in the older age groups the arterial events begin to predominate. Acute cardiovascular events, colon cancer and ovarian cancer all have a case fatality of about 50% within the first 5 years. Professor Heinemann summarized by stating that the incidence for cardiovascular and cancer conditions is much higher in industrialized countries, indicating a role of socio-economic and lifestyle factors. All noncommunicable diseases appear to share similar risk factors. The results of migration studies as well as the potential for prevention was discussed. The specific causal (initiating) risk factor (profile) for breast cancer is unknown. The breast cancer incidence and mortality in women older than 50 years is lower than for cardiovascular events. [ABSTRACT FROM AUTHOR]

In a brief review of the philosophical underpinnings of the ethics in science from Kant's categorical imperative to Fichte, Professor Poser outlined the main elements of the term "responsibility", which represents a complex situation. He described responsibility not only as a retrospective term in the sense of being responsible for past actions, but also as a prospective term which is directed into the future. He defined the responsible subject as the actor who in society (and in drug development) is replaced by a system of actors, each of whom takes responsibility according to his degree of involvement. "Informed consent" also turns a study subject into a responsible person, i.e. a carrier of responsibility. Expert panels are also actors in shared responsibility. The current ethical view holds that the activity for which responsibility is taken is governed by the intent of the action. Difficulties arise when unintended and unpredictable consequences of an intended activity occur. This raises questions about what is unpredictable and who is responsible if a consequence is unpredictable. The party to whom responsibility is owed, the object of responsibility, is an historically limited situation. It may be an individual, the law, society, God, future generations, or the totality of reasoning individuals. The reason for the existence of the concept of responsibility, finally, is based on values. These values may be functional, ethical, economic, or they may be based on other principles, such as conscience. Professor Poser interpreted the Helsinki declaration as an extension of Kant's principles. The declaration states that the risk taken by a human subject should be in a reasonable relationship to the value of the trial or experiment and that the rights or the human subject to physical integrity must be maintained. He closed by citing the Hippocratic dictum: nihil nocere, bonum facere. Clearly, these complex philosophical concepts determine how society perceives issues related to drug development and to drug risks and how society reacts both in an ethical and a legal sense. [ABSTRACT FROM AUTHOR]

Professor Teichmann outlined the historical development of HRT use and the current indications for use. He also discussed the motives and position of interested parties in the HRT setting, including the pharmaceutical industry, physicians, health politics, health insurance, and research institutes, each of which have their own perspective on HRT. [ABSTRACT FROM AUTHOR]