Menopause Live - IMS Updates

Date of release: 20 January, 2014

Exercise, breast size and cancer risk

At first glance, the new study by Williams [1] seemed, well, just another study showing how important physical activity is. Indeed, exercise reduces morbidity and mortality in a large list of diseases including cardiovascular, respiratory and oncological diseases. Clicking the key words 'breast cancer' and 'exercise' in PubMed yields about 2000 hits. So what's the point in commenting on this study? I guess it is because I liked its different way of looking at the issue. But first things first, and here are the core methods and findings [1]. Cox proportional hazard analyses were made of baseline pre-diagnosis MET-hours/week vs. breast cancer mortality adjusted for follow-up age, race, baseline menopause, and estrogen and oral contraceptive use in 79,124 women (32,872 walkers, 46,252 runners) from the National Walkers' and Runners' Health Studies. Women were categorized into three groups according to their level of exercise: below (< 7.5 metabolic equivalent h/week, MET-h/week), at (7.5–12.5 MET-h/week), or above (≥ 12.5 MET-h/week) recommended levels. Despite the large number of participants, only 111 women (57 walkers, 54 runners) died from breast cancer during the 11-year follow-up. The decline in mortality in women who exercised ≥ 7.5 MET-h/week was not different for walking and running (p  =  0.34), so running and walking energy expenditures were combined. The risk for breast cancer mortality was 41.5% lower for ≥ 7.5 vs. < 7.5 MET-h/week (hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.38–0.92, p =  0.02), which persisted when adjusted for body mass index (BMI) (HR 0.58, 95% CI 0.37–0.96, p  =  0.03). Other than age and menopause, baseline bra cup size was the strongest predictor of breast cancer mortality, i.e. 57.9% risk increase per cup size when adjusted for MET-h/week and the other covariates (HR 1.58, 95% CI 1.27–1.97, p < 0.0001), and 70.4% greater when further adjusted for BMI (HR 1.70, 95% CI 1.34–2.2, p  =  0.0005). Breast cancer mortality was 4.0-fold greater for C-cup, and 4.7-fold greater for ≥ D-cup vs. A-cup when adjusted for BMI and other covariates. Adjustment for cup size and BMI did not eliminate the association between breast cancer mortality and ≥ 7.5 MET-h/week walked or run (HR 0.61, 95% CI 0.39–1.00, p  =  0.05). The final conclusions were that breast cancer mortality decreased in association with both meeting the exercise recommendations and smaller breast volume.


Friedenreich has summarized 73 studies in which the average reduction in breast cancer risk, when comparing the most to the least physically active women, was 25%. There was also evidence for a dose–response effect found in the majority of studies that examined this trend [2]. The strongest associations were found for recreational and household activities and for activity that was of at least moderate intensity and sustained over a lifetime. There was also some evidence for a stronger effect of physical activity amongst postmenopausal women, women who are normal weight, have no family history of breast cancer, and are parous. The suggested mechanisms by which exercise could induce this preventive effect were linked to adiposity, sex hormones, insulin resistance, adipokines, and chronic inflammation.
The current study protocol involved two interesting variables: the exercise measurement and the association with bra cup size [1]. According to the author, running and walking exercise energy expenditures can be calculated from weekly distance run or walked, which appears to be a better metric for studying dose-response than the traditional time-based calculations used by other studies [3]. The previous experience of the author demonstrated that associations of body weight, diabetes, hypertension, and high cholesterol with distance-based estimates of energy expenditure were approximately two-fold larger than those observed with time-based estimates. Thus the author favors achieving a goal of a certain total energy expenditure per week, rather than the traditional recommendation of exercising three to four times weekly for at least 30 minutes of moderate intensity. Asking women to submit their bra cup size, a simple way to estimate breast volume, and using it for the prediction of breast cancer risk, had already been mentioned in the literature many years ago [4]. In a fairly large study, women were asked to report on their bra dimensions (cup and back size) prior to a first birth or at the age of 20 for nulliparous women. Among those reporting a chest size under 34 inches, multivariate-adjusted relative risks for breast cancer were 1.34 (95% CI 1.04–1.74) for cup size B, and 1.76 (95 CI 1.04–3.01) for cup size C and larger, compared to a cup size smaller than B, and the trend for increasing cup size was statistically significant (p = 0.005). There was no relation with breast size among women reporting an average or larger back circumference (34 inches or larger). The Nurses' Health Study reported on similar results in premenopausal women [5]. Bra cup size at age 20 was assessed among 89,268 women aged 29–47 in 1993. Subsequent incident cases of invasive breast cancer were assessed until 2001. During 622,732 person-years of follow-up, 803 premenopausal women were newly diagnosed with invasive breast cancer. For women with a BMI below 25 kg/m2, those with a bra cup size of 'D or larger' had a significantly higher incidence of breast cancer than women who reported 'A or smaller' cup size (covariate adjusted HR 1.80, 95% CI 1.13–2.88, p trend = 0.01). There was no significant association among women with a BMI of 25 kg/m2 or higher.
So what did I like in the index study? Simplicity. It is easy to report on the total time spent in exercise per week and the general nature of exercise (gardening, walking, running), than keeping an exact diary for each and every bout of physical activity. Also, one may assume that any women would remember correctly her bra cup size at youth even many years later on, thus allowing a good estimation of her breast volume without a significant recall bias. Realizing that these two parameters may be important as risk factors for future breast cancer, and their potential co-associations in predicting this risk, adds another perspective to be considered while evaluating the relevant individual risk profile status.


Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

El siguiente comentario es una traduccin de una contribucin original en Ingls enviada a los miembros el Abril 8, 2013. La traduccin ha sido gentilmente efectuada por el

Dr Peter Chedraui

El lupus eritematoso, artritis reumatoide y menopausia

Es muy importante comprender el impacto de la menopausia y el declinar androgénico relacionado a la edad con el inicio y el curso de las enfermedades autoinmunes, así como el potencial de las intervenciones hormonales [1]. En las mujeres, el curso del lupus eritematoso sistémico (LES) y la artritis reumatoide (AR) con inicio luego de establecida la menopausia difiere de aquella con el inicio antes de la menopausia. La edad temprana de la menopausia se asocia con mayor riesgo de enfermedad y, después de la menopausia, el curso de la enfermedad cambia en el LES y la AR. Este artículo resume lo que se sabe sobre la relación entre el envejecimiento reproductivo y las enfermedades autoinmunes en los hombres y mujeres, y destaca las áreas para una mayor investigación.


Esta revisión integral abarca hombres y mujeres, y se refiere a las interacciones de las hormonas sexuales con curso de la enfermedad y resultante [1]. Me centraré únicamente en los datos pertinentes a mujeres menopáusicas (sección 3 del artículo). La disminución de los niveles de estrógeno y de sulfato de DHEA puede estar asociada con un aumento en la producción de citoquinas pro-inflamatorias (IL-1, IL-6, TNF-α), y aumento de la respuesta fisiológica a estas citoquinas, disminución de la secreción de citocinas anti-inflamatorias (INF-γ), disminución de los niveles de linfocitos (células T y CD4 +) y disminución de la actividad citotóxica de las células asesinas naturales. El autor aporta datos en tres enfermedades que se sabe que son preponderantes en las mujeres – LES, AR y la esclerosis múltiple. En el Estudio de la Salud de las Enfermeras, una edad temprana de la menopausia, especialmente quirúrgica, se asoció con un mayor riesgo de desarrollar LES [2]. Varios estudios longitudinales, tales como el LUMINA [3], han observado disminución de la frecuencia de actividad lúpica después de la menopausia, modesta disminución del Índice de Actividad de la Enfermedad LES, pero mayor daño en los órganos afectados por actividad lúpica individual en el periodo postmenopáusico. En el Estudio de la Salud de las Enfermeras, el uso de hormonas postmenopáusicas 2 o más años se asoció a un aumento del riesgo de desarrollar LES [2], y varias publicaciones han apuntado a un curso más grave en usuarias de hormonas, sobre todo en aquellas que tomaron terapia combinada de estrógenos–progestina [4]. Sin embargo, el estudio LUMINA no demostró un aumento del riesgo de eventos vasculares arteriales o trombóticos venosos en usuarias de hormonas, pero la cohorte fue relativamente pequeña [5]. El tromboembolismo es importante en este contexto, ya que una fracción de los pacientes con LES tienen anticuerpos antifosfolípidos y la tendencia a formar coágulos de sangre. Otro estudio relativamente pequeño de México, donde las mujeres se asignaron al azar a la terapia hormonal o un placebo, llegó a la conclusión de que, a lo largo de 24 meses de seguimiento, la actividad de la enfermedad se mantuvo leve y estable y no se observó ninguna diferencia clínicamente significativa entre los grupos de tratamiento [6]. Tres pacientes en el grupo de tratamiento activo desarrollaron trombosis, una venosa y dos arteriales, pero uno de las anteriores tenía antecedente de trombosis. Una paciente del grupo placebo desarrolló trombosis arterial; por tanto, no hay más que deducirse de estos resultados. Los datos en lo que se refiere a la AR probablemente son más complejos. Una gran base de datos, presentada por Pikwer y colegas, demostró que una edad más tardía de inicio de la menopausia se asociaba a un menor riesgo de AR (riesgo relativo: 0.64; menopausia edad > 51 años vs. < 45 años) [7]. Esto era cierto tanto para las AR sero-negativas, y tal vez seropositivas. Pero, por otro lado, la menopausia precoz se asoció con una forma más leve de AR [8]. Estos hallazgos sugieren que la exposición a los estrógenos puede ser protectora contra la aparición de la enfermedad, sin embargo, el inicio temprano de la menopausia puede asociarse a una mayor proporción de pacientes que presenten un curso más leve de la enfermedad. Mientras un estudio más antiguo aleatorizado, controlado con placebo sugiere un posible efecto beneficioso de la terapia hormonal (medida como actividad de la enfermedad y escala de dolor) en mujeres cumplidoras [9], la Iniciativa de Salud de la Mujer mostró una reducción no significativa en el riesgo de desarrollar AR (razón de riesgo 0.74), una mejora no significativa en las puntuaciones de dolor en las articulaciones (odds ratio 4.1) sin ningún cambio en la inflamación [10]. El efecto protector de las hormonas sobre los huesos en la AR es sin duda, otro aspecto beneficioso que debe ser considerado. El lupus eritematoso sistémico y la artritis reumatoide son mucho más frecuentes en mujeres que en hombres. La comprensión de la compleja interacción entre la senescencia reproductiva y el curso de las enfermedades autoinmunes es de gran importancia. Los efectos de la terapia hormonal en el inicio y curso del LES o la AR, si acaso alguno, parecen modestos.

Amos Pines

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel


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