Cognitive Impairment, Aromatase Inhibitors, and Age

Abstract

TO THE EDITOR: The recommendations published in the January issue of the Journal of Clinical Oncology 1 regarding the use of aromatase inhibitors (AIs) confirm the advantages of using this drug in the adjuvant setting, and at the same time, underline the importance of monitoring the possible side effects, particularly for the subgroup of women for whom the risks and inconvenience of AI could outweigh the potential benefits.One of the most common side effects following AI therapy that can have repercussions on the patient's quality of life, is bone fracturing, 2 which is attributed to the reduced level (systemic and local) of estrogen as determined by the treatment. 3,4 In fact, this estrogen deficiency reduces bone mineral density and causes osteoporosis, bone fractures, hot flushes, and arthritic discomfort. It has also recently been reported to have an effect on cognitive status, and in particular, short and long-term memory, which is correlated with estrogen deficiency. 5 Estrogen receptors (ERs), including ER-␣ and ER-␤, are located throughout the brain, especially in the areas involved in learning and memory, such as the hippocampus and amygdala. 6 The enzymes necessary for sex steroid biosynthesis have been identified in these same areas, suggesting that estrogen has an important role in the brain. 7 Estrogen therapy has been one of the most compelling potential strategies for the prevention of dementia. The results from different studies suggest that hormonal therapy exerts its protective effect when used in the very early phases of the disease process or even before the disease begins. At the same time, because mild cognitive impairment frequently progresses to dementia, 8 preventative action becomes a relevant issue, especially for elderly patients. In fact, age itself, through the reduction of estrogen exposure and the presence of comorbidities, can promote cognitive impairment, which is strictly correlated with the loss of independence in elderly patients.The preliminary data on AI assumption suggests a possible impact on cognitive function: 94 women enrolled in the ATAC study and 35 healthy women were evaluated for cognitive function, after controlling for age and the use of hormone-replacement therapy. The women who received hormonal therapy manifested an impairment of verbal memory (P ϭ .026) and task processing speed (P ϭ .032). 9 Preliminary results from the TEAM (tamoxifen versus ex-

Neuropsychological functioning in postmenopausal breast cancer patients treated with tamoxifen or exemestane after AC-chemotherapy: Cross-sectional findings from the neuropsychological TEAM-side study

“…From our data, a different picture arises, suggesting that tamoxifen is associated with worse verbal functioning while exemestane negatively is associated with worse manual motor speed. Because a negative impact on musculoskeletal function has been described for aromatase inhibitors [4], it is possible that motor speed-deficits in exemestane users are rather a musculoskeletal feature than a cognitive problem. So, this should be taken into account in further cognitive studies.…”

“…As a result of increasing knowledge about the possible effects of estrogens on the brain and cognitive functioning, it has been questioned whether and how adjuvant hormonal therapies for BC are affecting cognitive functions [4,5]. Possibly beneficial effects of estrogens on brain function may be among others the result of estrogenic activity through estrogen receptors (ER) in brain regions that are important for cognitive functioning, effects on neurotransmitters, protection against ischemic damage and increased survival of brain cells [6].…”

Brain Endogenous Estrogen Levels Determine Responses to Estrogen Replacement Therapy via Regulation of BACE1 and NEP in Female Alzheimer’s Transgenic Mice

“…Studies have demonstrated a better verbal memory in women with longer endogenous estrogen exposure (3–4), while blockage of estrogen syntheses impairs cognitive function in breast cancer patients that have been treated with an aromatase inhibitor (5). Similarly, postmenopausal women treated with 17β-estradiol (E2), a natural form of estrogen, showed improvement on learning and memory functions (6–7), while conjugated equine estrogen (CEE), a synthetic form of estrogen, caused reduction of cognitive activities and increased risk of dementia as reported in various clinical trials, including the Women’s Health Initiative (WHI) studies (8–11).…”

Place actuelle des inhibiteurs de l'aromatase dans le traitement adjuvant des cancers du sein

“…L'extension de l'étude MA-17 qui randomise les patientes volontaires arrivées au terme de 5 ans de LET entre 5 ans d'IA supplémentaire et un bras placebo apportera des données supplémentaires sur cette question [23]. Il conviendra toutefois de porter une attention toute particulière aux effets secondaires potentiels des IA administrés à long terme en particulier sur le plan osseux, cardiovasculaire et cérébro-vasculaire, et également au retentissement potentiel sur les fonctions cognitives, en particulier chez les personnes âgées, qui a été très peu exploré jusqu'à présent [24].…”