Swiss national guideline for reimbursement of enzyme replacement therapy in late-onset Pompe disease.

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.

EMAS position statement: Testosterone replacement therapy in the aging male‏.

INTRODUCTION Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate. AIMS The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks. MATERIALS AND METHODS Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment.

Narrative review of changing medical and feminist perspectives on menopause : from femininity and ageing to risk and choice

Meanings and descriptions of menopause have shifted focus over the past century and a half; more particularly the past sixty years has seen a shift from descriptions of hormone decline and its relation to ageing, femininity and symptoms of menopause since the 1960's to the possibility for preventive medicine afforded by menopause. Medicine is not a static field in its construction of menopause. It has changed, not least by its engagement (positively or negatively) with critique from both within (epidemiological) and without (feminist and social sciences). In this review we identify three recent changes: (1) Increasing concern with women's decision-making. (2) The emergence from within medicine of the rejection of the use of language which defines menopause as a condition of deficiency. (3) New insights from postmodern and poststructural analyses of menopause that examine the epistemological foundations of medical and feminist concepts of menopause and contest fixed descriptions of the experience of menopause. Key aspects of a ‘medical menopause’ nevertheless remain constant: menopause is a loss of hormones that results in predictable effects and risks and may be ameliorated by hormone replacement therapy. A question therefore emerges about how and to what effect medical practitioners have engaged with critiques of the medical menopause?

Feminist ethics and menopause : autonomy and decision-making in primary medical care

The construction of menopause as a long-term risk to health and the adoption of discourses of prevention has made necessary a decision by women about medical treatment; specifically regarding the use of hormone replacement therapy. In a study of general practitioners’ accounts of menopause and treatment in Australia, women's ‘choice’, ‘informed decision-making’ and ‘empowerment’ were key themes through which primary medical care for women at menopause was presented. These accounts create a position for women defined by the concept of individual choice and an ethic of autonomy. These data are a basis for theorising more generally in this paper. We critically examine the construct of ‘informed decision-making’ in relation to several approaches to ethics including bioethics and a range of feminist ethics. We identify the intensification of power relations produced by an ethic of autonomy and discuss the ways these considerations inform a feminist ethics of decision-making by women. We argue that an ‘ethic of autonomy’ and an ‘offer of choice’ in relation to health care for women at menopause, far from being emancipatory, serves to intensify power relations. The dichotomy of choice, to take or not to take hormone replacement therapy, is required to be a choice and is embedded in relations of power and bioethical discourse that construct meanings about what constitutes decision-making at menopause. The deployment of the principle of autonomy in medical practice limits decision-making by women precisely because it is detached from the construction of meaning and the self and makes invisible the relations of power of which it is a part.

Menopause as a long-term risk to health : implications of general practitioner accounts of prevention for women’s choice and decision-making

Over the past two decades medical researchers and modernist feminist researchers have contested the meaning of menopause. In this article we examine various meanings of menopause in major medical and feminist literature and the construction of menopause in a semi-structured interview study of general practitioners in rural South Australia. Three discursive themes are identified in these interviews; (i) the hormonal menopause – symptoms, risk, prevention; (ii) the informed menopausal woman; and (iii) decision-making and hormone replacement therapy. By using the discourse of prevention, general practitioners construct menopause in relation to women's health care choices, empowerment and autonomy. We argue that the ways in which these concepts are deployed by general practitioners in this study produces and constrains the options available to women. The implications of these general practitioner accounts are discussed in relation to the proposition that medical and feminist descriptions of menopause posit alternative but equally-fixed truths about menopause and their relationship with the range of responses available to women at menopause. Social and cultural explanations of disease causality (c.f.Germov 1998, Hardey 1998) are absent from the new menopause despite their being an integral part of the framework of the women's health movement and health promotion drawn on by these general practitioners. Further, the shift of responsibility for health to the individual woman reinforces practice claims to empower women, but oversimplifies power relations and constructs menopause as a site of self-surveillance. The use of concepts from the women's health movement and health promotion have nevertheless created change in both the positioning of women as having ‘choices’ and the positioning of some general practitioners in terms of greater information provision to women and an attention to the woman's autonomy. In conclusion, we propose that a new menopause has evolved from a discursive shift in medicine and that there exists within this new configuration, claiming the empowerment of women as an integral part of health care for menopause, the possibility for change in medical practice which will broaden, strengthen, and maintain this position.

Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and Δ4-tibolone

Medroxyprogesterone acetate (MPA) has widely been used in hormone replacement therapy (HRT), and is associated with an increased risk of breast cancer, possibly due to disruption of androgen receptor (AR) signaling. In contrast, the synthetic HRT Tibolone does not increase breast density, and is rapidly metabolized to estrogenic 3α-OH-tibolone and 3β-OH-tibolone, and a delta-4 isomer (Δ4-TIB) that has both androgenic and progestagenic properties. Here, we show that 5α-dihydrotestosterone (DHT) and Δ4-TIB, but not MPA, stabilize AR protein levels, initiate specific AR intramolecular interactions critical for AR transcriptional regulation, and increase proliferation of AR positive MDA-MB-453 breast cancer cells. Structural modeling and molecular dynamic simulation indicate that Δ4-TIB induces a more stable AR structure than does DHT, and MPA a less stable one. Microarray expression analyses confirms that the molecular actions of Δ4-TIB more closely resembles DHT in breast cancer cells than either ligand does to MPA.

Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers

Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other pharmacologic interventions in a preclinical model of high MD.

Cost effectiveness of bone density measurements

Objective. To assess the cost-effectiveness of bone density screening programmes for osteoporosis. Study design. Using published and locally available data regarding fracture rates and treatment costs, the overall costs per fracture prevented, cost per quality of life year (QALY) saved and cost per year of life gained were estimated for different bone density screening and osteoporosis treatment programmes. Main outcome measures. Cost per fracture prevented, cost per QALY saved, and cost per year of life gained. Results. In women over the age of 50 years, the costs per fracture prevented of treating all women with hormone replacement therapy, or treating only if osteoporosis is demonstrated on bone density screening were £32,594 or £23,867 respectively. For alendronate therapy for the same groups, the costs were £171,067 and £14,067 respectively. Once the background rate of treatment with alendronate reaches 18%, bone density screening becomes cost-saving. Costs estimates per QALY saved ranged from £1,514 to £39,076 for osteoporosis treatment with alendronate following bone density screening. Conclusions. For relatively expensive medications such as alendronate, treatment programmes with prior bone density screening are far more cost effective than those without, and in some circumstances become cost-saving. Costs per QALY of life saved and per year of life gained for osteoporosis treatment with prior bone density screening compare favourably with treatment of hypertension and hypercholesterolemia.

Polymorphic low penetrance genes and breast cancer : The role of genes involved in metabolism of xenobiotics, estrogens and reactive oxygen species

Various endogenous and exogenous factors have been reported to increase the risk of breast cancer. Many of those are related to prolonged lifetime exposure to estrogens. Furthermore, a positive family history of breast cancer and certain benign breast diseases are known to increase the risk of breast cancer. The role of lifestyle factors, such as use of alcohol and smoking has been an area of intensive study. Alcohol has been found to increase the risk of breast cancer, whereas the role of smoking has remained obscure. A multitude of enzymes are involved in the metabolism of estrogens and xenobiotics including the carcinogens found in tobacco smoke. Many of the metabolic enzymes exhibit genetic polymorphisms that can lead to inter-individual differences in their abilities to modify hazardous substrates. Therefore, in presence of a given chemical exposure, one subgroup of women may be more susceptible to breast carcinogenesis, since they carry unfavourable forms of the polymorphic genes involved in the metabolism of the chemical. In this work, polymorphic genes encoding for cytochrome P450 (CYP) 1A1 and 1B1, N-acetyl transferase 2 (NAT2), sulfotransferase 1A1 (SULT1A1), manganese superoxide dismutase (MnSOD) and vitamin D receptor (VDR) were investigated in relation to breast cancer susceptibility in a Finnish population. CYP1A1, CYP1B1 and SULT1A1 are involved in the metabolism of both estrogens and xenobiotics, whereas NAT2 is involved only in the latter. MnSOD is an antioxidant enzyme protecting cells from oxidative damage. VDR, in turn, mediates the effects of the active form of vitamin D (1,25(OH)2D3, calcitriol) on maintenance of calcium homeostasis and it has anti-proliferative effects in many cancer cells. A 1.3-fold (95% CIs 1.01-1.73) increased risk of breast cancer was seen among women who carried the NAT2 slow acetylator genotype and a 1.5-fold (95% CI 1.1-2.0) risk was found in women with a MnSOD variant A allele containing genotypes compared to women with the NAT2 rapid acetylator genotype or to those with the MnSOD VV genotype, respectively. Instead, women with the VDR a allele containing genotypes were found to be at a decreased risk for breast cancer (OR 0.73; 95% CI 0.54-0.98) compared to women with the AA genotype. No significant overall associations were found between SULT1A1 or CYP genotypes and breast cancer risk, whereas a combination of the CYP1B1 432Val allele containing genotypes with the NAT2 slow acetylator genotypes posed a 1.5-fold (95% CI 1.03-2.24) increased risk. Moreover, NAT2 slow acetylator genotype was found to be confined to women with an advanced stage of breast cancer (stages III and IV). Further evidence for the association of xenobiotic metabolising genes with breast cancer risk was found when active smoking was taken into account. Women who smoked less than 10 cigarettes/day and carried at least one CYP1B1 432Val variant allele, were at 3.1-fold (95% CI 1.32-7.12) risk of breast cancer compared to women who smoked the same amount but did not carry the variant allele. Furthermore, the risk was significantly increased with increasing number of the CYP1B1 432Val alleles (p for trend 0.005). In addition, women who smoked less than 5 pack-years and carried the NAT2 slow acetylator genotype were at a 2.6-fold (95% CI 1.01-6.48) increased risk of breast cancer compared to women who smoked the same amount but carried the NAT2 rapid acetylator genotype. Furthermore, the combination of the CYP1B1 432Val allele and the NAT2 slow acetylator genotype increased the risk of breast cancer by 2.5-fold (95% CI 1.11-5.45) among ever smokers. Instead, the MnSOD A allele was found to be a risk factor among postmenopausal long-term smokers (>15 years of smoking) (OR 5.1; 95% CI 1.4-18.4) or among postmenopausal women who had smoked more than 10 cigarettes/day (OR 5.5; 95% CI 1.3-23.4) compared to women who had similar smoking habits but carried the MnSOD V/V genotype. Similarly, within subgroups of postmenopausal women who were using oral contraceptives, hormone replacement therapy or alcohol, women carrying the MnSOD A allele genotypes seemed to be at increased risk of breast cancer compared to women with the MnSOD V/V genotype. A positive family history of breast cancer and high parity were shown to be inversely associated with breast cancer risk among women carrying the VDR ApaI a allele or among premenopausal women carrying the SULT1A1*2 allele, respectively.

Osteoporosis medication dispensing for older Australian women from 2002 to 2010: Influences of publications, guidelines, marketing activities and policy

Purpose Developments in anti-osteoporosis medications (AOMs) have led to changes in guidelines and policy, which, along with media and marketing strategies, have had an impact upon the prescribing of AOM. The aim was to examine patterns of AOM dispensing in older women (aged 76–81 years at baseline) from 2002 to 2010. Methods Administrative claims data were used to describe AOM dispensing in 4649 participants (born in 1921–1926 and still alive in 2011) in the Australian Longitudinal Study on Women's Health. The patterns were interpreted in the context of changes in guidelines, indications for subsidy, publications (scholarly and general media), and marketing activities. Results Total use of AOM increased from 134 DDD/1000/day in 2002 to 216 DDD/1000/day in 2007 but then decreased to 184 DDD/1000/day in 2010. Alendronate was the most commonly dispensed AOM but decreased from 2007, while use of risedronate (2002 onward), strontium ranelate (2007 onward) and zoledronic acid (2008 onward) increased. Etidronate and hormone replacement therapy (HRT) prescriptions gradually decreased over time. The decline in alendronate dispensing coincided with increases of other bisphosphonates and publicity about potential adverse effects of bisphosphonates, despite relaxing indications for bone density testing and subsidy for AOM. Conclusions Overall dispense of AOM from 2002 reached a peak in 2007 and thereafter declined despite increases in therapeutic options and improved subsidised access. The recent decline in overall AOM dispensing seems to be explained largely by negative publicity rather than specific changes in guidelines and policy.

Diagnóstico de um grupo de familiares em risco para o câncer de mama: contribuição para a assistência de enfermagem

Devido a sua alta incidência, mortalidade e custos elevados, o câncer de mama feminino é considerado um problema de saúde pública no Brasil. Sua etiologia envolve uma interação de diversos fatores denominados de risco os quais podem ser ambientais e genéticos. A história familiar positiva para câncer de mama é um importante fator de risco para o desenvolvimento dessa patologia. Conhecer esses fatores e as medidas de proteção permite que mulheres com risco elevado possam criar estratégias pessoais que venham minimizar os danos causados pela doença. Diante do exposto, o presente estudo tem como objetivos avaliar o nível de conhecimento de mulheres acerca do risco de desenvolverem câncer de mama em decorrência do vínculo familiar com a população portadora desta neoplasia matriculada no Hospital do Câncer III, unidade do Instituto Nacional de Câncer (INCA) especializada no tratamento e controle do câncer de mama, localizada no município do Rio de Janeiro, Brasil; descrever as características sociodemográficas das mulheres familiares de pacientes portadoras de câncer de mama e descrever a história reprodutiva e hormonal, bem como seus hábitos de cuidado com a saúde. Metodologia: trata-se de um estudo exploratório sob a perspectiva quantitativa, transversal e descritiva com 52 mulheres que acompanhavam suas familiares internadas em unidade clínica e cirúrgica do Hospital do Câncer III. A coleta de dados ocorreu no período entre julho e agosto de 2011. A técnica de amostragem adotada foi a não probabilística, intencional Para o cálculo amostral aplicou-se a fórmula de população infinita. Foram selecionadas as seguintes variáveis para compor o estudo: aspectos sociodemográficos, aspectos da vida reprodutiva e hormonal, aspectos de cuidados com a saúde e aspectos de esclarecimento relacionados à patologia/doença. Realizou-se entrevista estruturada com utilização de um formulário composto por 63 questões. A descrição das variáveis foi feita através de frequência simples e porcentagem. Resultados: 61,5% eram filhas, 34,6% eram irmãs e 3,8% eram mães, 40,4% moram no município do Rio de Janeiro, 86,4% encontram-se na faixa etária entre 29 e acima de 51 anos de idade, 32% são pardas, 46,1% apresentavam 2 grau completo, 46,2% são do lar, 15,4% tiveram menarca precoce, 7,7 % tiveram na menopausa tardia, 7,7% fizeram Terapia de Reposição Hormonal, 38,5% nunca engravidaram, 3,8% engravidaram após 30 anos, 3,8% não amamentaram, 42,4% usam anticoncepcional hormonal por mais de 5 anos e 40,4% nunca fizeram descanso ou faz por tempo inferior a 6 meses, 7,7% e 7,6% nunca fizeram e apresenta mais de 24 meses que fizeram exame ginecológico. Quanto ao grau de esclarecimento 34% concordaram com as afirmativas sobre fatores de risco, 65% concordaram com medidas preventivas e os profissionais de saúde foram os que mais transmitiram informação sobre o câncer de mama. Conclusão: ser familiar de primeiro grau associado à falta de esclarecimento sobre a doença torna essas mulheres mais vulneráveis em relação à população geral feminina. Torna-se oportuno para a enfermagem estratégias educativas que visem à promoção da saúde e que contribuam para a modificação do panorama da doença, em razão da detecção mais precoce.

Efeitos do tratamento prolongado com isoflavonas de soja no útero, mamas, tecidos adiposo e ósseo de ratas ovariectomizadas

A menopausa, fenômeno fisiológico que ocorre em todas as mulheres, em média, aos 51 anos, é acompanhada em cerca de 80% dos casos de sintomas como fogachos, secura vaginal, irritabilidade e insônia, que interferem na qualidade de vida e na produtividade socioeconômica das mulheres, além de predispô-las a doenças crônico-degenerativas, como arteriosclerose, obesidade e distúrbios cardiovasculares. A terapia de reposição hormonal à base de estrógenos, que visa reduzir os incômodos da menopausa, está associada ao aumento do risco de câncer de mama e do endométrio, como foi demonstrado em estudos científicos. Considerando que as mulheres orientais, consumidoras de soja, apresentam doenças crônico-degenerativas e câncer em taxas inferiores às dos países ocidentais, as isoflavonas da soja têm sido testadas em estudos clínicos e experimentais, porém com obtenção de dados até contraditórios. O presente estudo investigou o efeito da administração crônica de isoflavonas de soja no útero, mamas e tecidos adiposo e ósseo de ratas ovariectomizadas. Quarenta ratas Wistar adultas foram distribuídas em quatro grupos experimentais: a) ovariectomizadas: grupo ISO, recebendo isoflavonas de soja (100mg/kg/dia/v.o.); b) ovariectomizadas: grupo BE, recebendo benzoato de estradiol (10g/kg/dia/s.c.); c) ovariectomizadas: grupo OVX, recebendo salina (0,1ml/100g/dia/v.o.); d) controles: grupo FO, recebendo salina (0,1ml/100g/dia/v.o.). Antes e durante os 90 dias de tratamento, foram analisados os esfregaços vaginais, para acompanhamento do ciclo estral, determinação do peso corporal e do consumo de ração semanal. Após esse período, os animais foram anestesiados e o sangue coletado para análise de estradiol e progesterona séricos, por radioimunoensaio; e lipidograma e glicose, por espectrofotometria. Posteriormente, os animais foram sacrificados e necropsiados, coletando-se o útero, mamas, gordura intra-abdominal e fêmur para macroscopia e pesagem. Os tecidos selecionados para o estudo foram corados em HE, analisados por microscopia óptica e histomorfometria, visando investigar alterações do crescimento celular (software V.S NIH Image-J; imagens digitais-optronicos CCD). No grupo tratado com isoflavonas, o peso corporal diminuiu em relação OVX, no qual ocorreu aumento de peso em comparação aos animais falso-operados. O exame macroscópico revelou que o útero diminuiu de peso nas ratas do grupo ISO, semelhante às do OVX. Além disso, a histopatologia das glândulas endometriais não mostrou alterações entre os grupos ISO e OVX. Contudo, o grupo BE apresentou proliferação glandular, pseudoestratificação epitelial, frequentes mitoses típicas, metaplasia escamosa, infiltrado eosinofílico e hidrométrio. A concentração de estradiol no grupo ISO foi semelhante à do OVX. Porém, no grupo BE, o estradiol e o peso uterino apresentaram-se aumentados em relação ao OVX. Não foram observadas diferenças na histomorfometria mamária entre os grupos. Houve redução no peso do tecido adiposo abdominal no grupo ISO, comparado com o OVX, sem identificação de alterações morfológicas significativas, apenas hipotrofia celular, confirmada pela histomorfometria. Apesar de não ter havido diferenças na concentração de glicose, colesterol total e triglicerídeos, entre os grupos, o colesterol-HDL apresentou aumento no grupo ISO. Não houve diferença na densitometria do fêmur entre os grupos avaliados. Esses resultados indicam que o tratamento crônico com isoflavonas de soja, na dose testada, não induz mudanças significativas no útero, mamas e tecidos adiposo e ósseo, sugerindo segurança no tratamento, sem risco para o desenvolvimento de câncer.