Terapia hormonal de reemplazo en prevención cardiovascular: ¿Dónde estamos parados? / Hormone replacement therapy and cardiovascular prevention: Where are we now?

Durante su edad fértil, la mujer sufre una incidencia de enfermedad cardiovascular ateroesclerótica (particularmente infarto de miocardio) significativamente inferior a la del hombre. Este beneficio desaparece progresivamente luego de la menopausia, hasta equilibrarse luego de la sexta década de la vida. Estudios experimentales en modelos animales y humanos sugirieron la existencia de mecanismos fisiológicos por los cuales los estrógenos podrían ser los responsables de esta protección cardiovascular, y análisis retrospectivos de estudios clínicos mostraron que las mujeres climatéricas que habían consumido terapia hormonal de reemplazo (THR) sufrían menos eventos cardiovasculares. Estas observaciones estimularon la ejecución de numerosos ensayos clínicos prospectivos aleatorizados (algunos de gran envergadura) en mujeres climatéricas, destinados a probar la hipótesis de que la THR podría prevenir eventos cardiovasculares graves en esa población. La hipótesis no pudo probarse, ya que en ninguno de esos ensayos la THR fue efectiva, y en algunos casos incluso fue en ciertos aspectos perjudicial. Existen cuestionamientos de orden metodológico que tienen que ver con el diseño de dichos ensayos prospectivos, fundamentalmente la edad de las pacientes incluidas y el momento del inicio de la THR. Existen también razones biológicas que pueden explicar la mencionada contradicción. Una nueva hipótesis, basada asimismo en observaciones experimentales y clínicas, se orienta hacia la posibilidad de que el inicio de la THR en mujeres más jóvenes y más precozmente luego de la menopausia, podría mostrar diferentes resultados.

During their fertile period women suffer significantly less atherosclerotic cardiovascular disease (particularly myocardial infarction) than men. This benefit progressively disappears after menopause, to equalize after the sixth decade of life. Experimental studies in animal and human models demonstrated the existence of physiological mechanisms suggesting that estrogens could be responsible for this cardiovascular protection, and retrospective analysis of clinical studies showed that post menopausal women who had used hormonal replacement therapy (HRT) suffered less cardiovascular events. These observations stimulated the execution of several prospective, randomized clinical trials (some of them with a large number of patients and prolonged follow-up) in post menopausal women, with the aim of proving the hypothesis that HRT could prevent major cardiovascular events. Such hypothesis could not be demonstrated in any of those studies because HRT was not beneficial, and in several cases it was even deleterious in some aspects. Criticism has arisen over some of the methodological aspects of those prospective trials, basically regarding the age of the included patients and the timing of the beginning of HRT. There are also biological reasons that can explain the contradiction. A new hypothesis, also based on experimental and clinical observations, suggests the possibility that beginning HRT in younger women and earlier after menopause could yield different results.

Selective estrogen receptor modulators (SERMS) / Moduladores seletivos do receptor estrogênico (SERMs)

Hormone receptors and, specifically, estrogen receptors were described about four decades ago. For estrogens, there are two receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). The two receptors are coded by different genes and their tissue expression varies across organs. ERalpha is predominantly expressed in reproductive tissues (uterus, breast, ovaries) liver and central nervous system, whereas ERbeta is expressed in other tissues such as bone, endothelium, lungs, urogenital tract, ovaries, central nervous system and prostate. More than seventy molecules that belong to the SERMS class have been described. There are 5 chemical groups: triphenylethylenes, benzotiophenes, tetrahydronaphtylenes, indoles and benzopyrans. All of these non-hormonal compounds are capable of activating the ER, reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. Estrogens reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. They are also beneficial for the relief of menopausal symptoms. An ongoing debate that extends over the decades, relates to to overall benefit/risk profile of estrogen or estrogen-progestin therapy since these therapies can increase the risk of serious health disorders, such as breast cancer. SERMs have increased our understanding of hormone-receptor regulatory mechanisms. Their development has permitted a targeted efficacy profile avoiding some of the side effects of the hormone therapy. Their clinical utility relies today mostly on the effects on breast cancer and bone.

Os receptores hormonais e especificamente os receptores estrogênicos, foram descritos há cerca de 40 anos. Para os estrógenos, existem dois tipos: o alfa (ERalfa) e os beta (ERbeta), os quais são codificados por diferentes genes e sua expressão tissular varia de tecido para tecido. O ERalfa se expressa predominantemente no aparelho reprodutivo (útero, mamas, ovários), fígado e sistema nervoso central (SNC). O ERbeta se expressa em outros tecidos como osso, endotélio, pulmões, urogenital, além dos ovários, SNC e próstata. Mais de setenta moléculas pertencentes ao grupo dos SERMs têm sido descritas, em 5 grupos químicos: trifeniletilenos, benzotiofenos, tetrahidronaftilenos, indols e benzopiranos. Todos estes compostos não hormonais são capazes de ativar o ER, reduzindo a remodelação óssea e melhorando a densidade mineral óssea. Os estrógenos reduzem a remodelação óssea e aumentam a densidade mineral óssea, como também melhoram os sintomas da menopausa. Um debate permanente existe a respeito da relação risco/benefício da terapia estrógeno-progestínica, em virtude do aumento do risco de problemas de saúde mais sérios como câncer de mama. Os SERMs aprimoraram o conhecimento sobre os mecanismos de regulação hormônio-receptor, e o seu desenvolvimento permitiu uma eficiente modalidade de ação terapêutica hormonal, evitando-se alguns dos efeitois adversos da terapia hormonal per si.

Quimioprevencion del cancer de mama: ensayos clinicos en la prevencion farmacologica / Chemoprevention of breast cancer: clinical trials in pharmacological prevention

El presente artículo trata sobre los ensayos clínicos presentados en quimioprevención del cáncer mamario. Hasta la fecha las drogas más estudiadas han sido los Moduladores Selectivos de los Receptores de Estrógenos (SERMs). Cuatro estudios aleatorizados de tamoxifeno versus placebo fueron publicados y dos con raloxifeno están en curso. Dos de los estudios con tamoxifeno mostraron una reducción de incidencia de cáncer mamario entre el 30 y el 50%, sin embargo otros dos trabajos no mostraron diferencias estadísticamente significativas. A esta controversia se le suma la incertidumbre sobre el verdadero impacto en la mortalidad que pudiera tener este tipo de terapia preventiva. Se citan además diversos estudios que evaluaron la ingesta de vitaminas y su relación con el desarrollo de tumores mamarios. Sin duda alguna el estudio y el seguimiento de los ensayos clínicos nos permitirán dilucidar qué pacientes requieren una terapia, preventiva del desarrollo de un tipo específico de cáncer, que se encuentra lejos de estar exenta de riesgos.

Hormone replacement therapy and the risk of breast cancer: assessment of therapy acceptance in a cohort of previously treated breast cancer patients

INTRODUCTION: In the postmenopausal period, an average of 25 percent of women will present symptomatic ovarian failure requiring hormonal replacement therapy. Estrogen can relieve vasomotor symptoms. Hormonal replacement therapy is generally not recommended for breast cancer patients due to the potential risk of tumor recurrence. To answer the questions about the safety of hormonal replacement therapy in this subgroup of women, it is necessary to establish the acceptance of treatment. METHODS: Between September 1998 and February 2001, a cohort of 216 breast cancer patients were asked to complete a questionnaire. All patients had completed their treatment and were informed about survival rates after breast cancer and hormonal replacement therapy. RESULTS: Among the 216 patients, 134 (62 percent) would refuse hormonal replacement therapy. A hundred patients were afraid of relapse (74.6 percent). Adjuvant tamoxifen therapy was the only statistically significant variable (70.3 percent versus 29.7 percent p=0.003). Understanding clinical stage (p= 0.045) and type of medical assistance (private versus public , p=0.033) also seemed to influence the decision. Early stage disease (p= 0.22), type of surgical procedure (radical versus conservative, p=0.67), adjuvant chemotherapy (p=0.082) or marital status (p=0.98 ) were not statistically significant in decision making. Several patients submitted to adjuvant chemotherapy (41.6 percent) would accept hormonal replacement therapy under medical supervision, as did most of advanced clinical stage patients (58.3 percent; p=0.022). CONCLUSION: There is a high level of rejection for hormonal replacement therapy among breast cancer patients when current data on tumor cure rates, and potential risks of estrogen use is available. Adverse effects of tamoxifen in the adjuvant setting may be the reason for refusal of hormonal replacement therapy