[Remarks of the Zurich Discussion Panel on the gene test].
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Biomedical subjects
Publications and source records attributed to M Birkhäuser.
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This review discusses the effect of Oestrogens, Progestagens, Tibolone, Raloxifene and Phytooestrogens in postmenopausal women on the breast. Epidemiological statisticians are only speaking of a clinical significance if the relative risk is half (< 0.05) or doubled (> 2.0). All published data from observational studies or from important meta- and reanalyses concerning the relative risk of breast cancer in women using postmenopausal hormone therapy are within these limits and clearly below the risk observed in young smokers. The relative risk for breast cancer observed in the Womens Health Initiative (WHI) stays within these limits too, in women treated by a fix Oestrogen-Progestagen combination. However, in the WHI, there was no increase of the relative risk for breast cancer in women using oestrogens alone. The risk for breast cancer rises in parallel to the duration of the hormone treatment. The risk for hormone users to suffer from breast cancer does not increase earlier than 4-5 years after the start of the therapy. An important reanalysis reports, that after 5 years of hormone use, a breast cancer is diagnosed in 2 additional women out of 1000 (47 instead of 45 women). The absolute risk should be indicated in addition to the relative risk because, for non-specialists, the exclusive indication of the relative risk might be misleading. Following the results from the WHI and from some other, older studies, the relative risk for breast cancer might be higher in women taking an oestrogen-progestagen combination than in women using oestrogens alone. Experimental and preliminary clinical data on Tibolone and Raloxifene do not show a negative effect on breast tissue. However, if Tibolone and Raloxifene as well as Phytooestrogens possess a protective activity remains open because prospective randomized long-term clinical studies are still missing.
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The new hormonal contraceptives are safe, effective and with fewer side effects than the older formulations. Their incidence of serious complications is low, particularly as compared to the health risk related to pregnancy. Adolescents must be screened for contra-indications before giving them a hormonal contraceptive. Because pills do not prevent sexually transmitted diseases, teenagers should be counselled to use a barrier methods together with COCs. Young girls need frequent follow-up and close monitoring to minimise side effects and to increase compliance and continuation in use. Long-term contraception by implants represents a valid alternative option with an increasing popularity among adolescents.
Perimenopause, such as postmenopause, is a physiologic condition that could be accompanied by several symptoms that may need a medical intervention. Women need to be informed about the available therapeutic options, including no treatment at all if not necessary. Oral hormonal contraceptives represent a valid and safe option in healthy premenopausal women with complaints. They guarantee a safe and reliable contraception in women without contraindications. The alternatives to oral hormonal contraceptives are injectable progestagens, oral progestagen-only preparations, progestagen implants or progestagen-loaded IUD's. It is highly important to inform correctly the patient and make her to participate actively in the therapeutic decision. This educational process helps in building a solid relationship and improves patient adherence with better clinical results.
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A correct Hormone Replacement Therapy (HRT) guarantees a successful treatment of subjective symptoms of oestrogen deficiency and an efficient prevention of postmenopausal osteoporosis, of cardiovascular diseases and of M. Alzheimer. In non-substituted postmenopausal women, the risk to die from a myocardial infarction is ten times higher than the risk to die from a carcinoma of the breast or the consequences of a fracture of the femoral neck. In spite of this observation, the acceptance is still insufficient because of an unjustified fear of hormone-induced carcinomas. The incidence of a carcinoma of the breast is not higher in women profiting of a HRT by a correct combination of an oestrogen and a progestogen administered up to 5 years than in untreated controls. Although some but not all authors suspect a slight increase of the relative risk of a carcinoma of the breast to approximately 1.5 after > or = 10 years of HRT, the overall mortality of substituted women is clearly inferior to the one of a non-substituted population. However, the final goal of HRT is not prolongation of life, but a better quality of life. Quality of life is often miserable in women treated for breast cancer. The final answer to the question if women after treatment of breast cancer should be allowed to profit of HRT is still open because formal evidence is missing. However, a woman should not be denied HRT if she lived two years without relapse since her primary cancer and if she does not belong to the subgroup where adjuvant treatment by tamoxifen is appropriate. In the future, selective oestrogen receptor modulators may be used in women after breast cancer.
Up to recently women with a history of breast cancer were not allowed relief of menopausal symptoms with hormonal replacement therapy (HRT). The reasons for this attitude were the following: in vitro breast cancers are hormone-dependent tumours; the number of ovulatory cycles influences the risk of breast cancer; ovarectomy as an adjuvant measure after breast cancer is effective; anti-oestrogens are effective against breast cancer. Nowadays issues of quality of life have become more important and HRT has been reassessed in the light of the following considerations: there is no real alternative to HRT for severe menopausal symptoms; subsequent pregnancies (with concomitant high oestrogen levels) do not appear to worsen the prognosis of breast cancer; oestrogen therapy of metastatic breast cancer was described as a successful therapy in earlier times; up to now it has not been proved that HRT for a short period of time influences the risk of developing breast cancer; thus far several smaller studies of HRT after breast cancer have not demonstrated any worsening breast cancer prognosis; certain anti-oestrogens are very effective against breast cancer even though they also have a relevant tissue-specific oestrogenic activity. Furthermore, all the other positive effects of HRT (prevention of osteoporosis and lowering of the risk of myocardial infarction) are arguments for more liberal but controlled prescription of oestrogens. Until more is known about HRT after breast cancer we suggest treatment of menopausal symptoms in women with a history of breast cancer be given only within the HABITS study (HABITS: Hormonal replacement therapy after breast cancer diagnosis--is it safe?). This study has the support of the International Breast Cancer Study Group (IBCSG).
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The prescription of hormone replacement therapy (HRT) requires a pretherapeutic evaluation and an ongoing surveillance during treatment. Pretherapeutic evaluation identifies the indications and contraindications to HRT. It includes a clinical examination, a Papanicolaou smear, and other tests according to the clinical situation. Monitoring of HRT consists of a first follow-up visit 3 months after beginning treatment to assess the effectiveness, side effects, and compliance with the therapy. Following this, yearly medical examinations should be scheduled. This paper describes the most frequent clinical signs that suggest a modification of treatment or the need to perform further investigations.
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OBJECTIVES: The objectives were to compare the tolerability, adhesion and efficacy of a new matrix-type estradiol transdermal system, Oesclim 50, with those of Estraderm TTS 50, a reservoir-type system. METHODS: This was an open, randomised, parallel-group, multi-centre clinical trial, performed in six European countries. A total of 143 healthy menopausal women were allocated to treatment with Oesclim 50 and 140 to Estraderm TTS 50. The transdermal systems were applied twice weekly for 24 days out of each 28-day cycle, over a period of four cycles. Oral progestogen treatment was taken by non-hysterectomised patients for the last 12 days of estrogen therapy in each cycle. RESULTS: The local skin tolerability of the Oesclim 50 transdermal system was significantly better than that of Estraderm TTS 50. In the Oesclim 50 group, 4.2% of applications caused a reaction, compared with 9.5% in the Estraderm TTS 50 group (P < 0.001). Safety assessments showed both treatments to be well tolerated. Seven patients in the Oesclim 50 group, and 12 in the Estraderm TTS 50 group, discontinued due to adverse events. Of these discontinuations, one (0.7% of patients) in the Oesclim 50 group and seven (5.1% of patients) in the Estraderm TTS 50 group were due to application site reactions (P < 0.05). There was no statistically significant difference between the two groups in the percentage of patients with signs of hyperestrogenism (29 patients (20.3%) in the Oesclim group and 28 patients (20.0%) in the Estraderm TTS 50 group). Adhesion was significantly better for the Oesclim 50 transdermal system, with 6.0% of Oesclim 50 applications becoming detached compared with 11.3% of Estraderm TTS 50 applications (P < 0.001). The greater adhesion of Oesclim 50 was particularly apparent when the systems were exposed to water, with three times fewer Oesclim 50 systems becoming detached during a shower or bath (P < 0.001 in each case). Both treatments produced significant and comparable improvements in vasomotor symptoms, other menopausal symptoms and gynaecological assessments. A near-maximal effect on vasomotor symptoms was observed after approximately 1 month of treatment, and was maintained for the entire treatment period. CONCLUSION: Overall, Oesclim 50 provided statistically significantly better local skin tolerability and adhesion than Estraderm TTS 50, together with comparable efficacy and safety.
OBJECTIVES: The objectives were to compare the local skin tolerability of a matrix-type estradiol transdermal system, Oesclim 50, with that of the reservoir-type system, Estraderm TTS 50. METHODS: Two randomised studies were performed. In the first study, the modified Draize-Shelanski-Jordan method of sensitization was used in an open, parallel-group trial to compare the cutaneous tolerability of repeated applications of Oesclim 50 with that of Estraderm TTS 50 in 24 healthy postmenopausal women. The second study was an open, randomised, parallel-group, multi-centre clinical trial involving 283 healthy menopausal women. A total of 143 women were allocated to treatment with Oesclim 50 and 140 to Estraderm TTS 50. The treatment duration was four months. RESULTS: The first study showed that the treatments, Oesclim 50 and Estraderm TTS 50, had no sensitizing potential and did not induce allergic reactions. In the second study, 4.2% of applications in the Oesclim group provoked reactions compared with 9.5% in the Estraderm group (P < 0.001). Thirty-seven patients (25.9%) treated with Oesclim and 55 patients (39.9%) receiving Estraderm experienced one or more reactions (P < 0.05). Redness and itching were the most frequent types of application site reaction in both treatment groups. The durations of the reactions were significantly shorter in the Oesclim group (P < 0.01), with a higher percentage of durations of less than 1 h and a lower percentage of durations of over 48 h than in the Estraderm TTS 50 group. None of the reactions in the Oesclim group led to premature removal of the patch, compared with 11 (3.4%) in the Estraderm group (P < 0.05). The number of patients who discontinued treatment due to application site reactions was one (0.7%) in the Oesclim group and seven (5.1%) in the Estraderm group (P < 0.05). Efficacy and general safety were comparable in the two treatment groups. CONCLUSIONS: In the first study, neither Oesclim nor Estraderm induced allergic reactions. In the second study, the local skin tolerability of Oesclim was significantly better than that of Estraderm, in terms of the number, duration and severity of the application site reactions.