Effects of breast cancer treatment on the hormonal and cognitive consequences of acute stress Joseph M. Andreano 1 *, James Waisman 2,3 , Lisa Donley 3 and Larry Cahill 1 1 Center for the Neurobiology of Learning and Memory, Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA 2 Barbara K. Robinson Breast Cancer Research Group, Long Beach Memorial Medical Center, Long Beach, CA, USA 3 Breastlink Medical Group, Long Beach, CA, USA *Correspondence to: Center for the Neurobiology of Learning and Memory, Department of Neurobiology and Behavior, University of California, Irvine, California, 92697 USA. E ‐ mail: jandrean@uci.edu Received: 23 September 2010 Revised: 29 April 2011 Accepted: 10 May 2011 Abstract Background: Cognitive difficulties following treatment for breast cancer are frequently reported. Breast cancer treatments also disrupt the function of ovarian and glucocorticoid hor- mone systems, both of which can affect cognition. Methods: To assess the influence of glucocorticoid and ovarian disruption on cognitive dys- function, survivors of breast cancer treated with the GnRH agonist Lupron were compared with healthy controls on their glucocorticoid response to a physiological stressor, and their per- formance on various measures of cognition including working memory, verbal paired associate memory, and narrative recall. Results: The results indicated no significant glucocorticoid response to the stressor in Lupron‐ treated survivors, while the controls showed significantly elevated cortisol levels. Cognitive test- ing showed a general impairment of narrative recall in breast cancer survivors relative to controls, irrespective of stress treatment. When tested on an emotional narrative, controls ex- posed to post‐training stress showed a significant enhancement of emotional recall and a signif- icant relationship between cortisol release and subsequent memory. In contrast, post‐training stress produced no cognitive enhancement in survivors, and memory performance in this group showed no relationship to cortisol levels. Conclusions: These results suggest that a disruption of the enhancement of memory by stress may contribute to cognitive difficulties following breast cancer treatment. Copyright # 2011 John Wiley & Sons, Ltd. Keywords: cancer; oncology; endocrinology; Lupron; memory Introduction Cognitive impairment following treatment for breast cancer has been widely reported [1–6]. Deficits have been found over a broad range of cognitive domains, but difficulties in concentration and memory are most frequently reported by patients [7]. Meta‐analyses of controlled studies have also detected consistent effects of cancer treatment on working, verbal, and long‐term memory [8,9]. The cause of cognitive dys- function in breast cancer patients has not been fully characterized, but the majority of studies have assessed the cognitive effects of chemotherapy, [1,2,4–6]. Although converging evidence suggests that chemotherapy can have lasting cognitive conse- quences [8,9], substantial variance in cognitive out- comes exists, suggesting that other factors contribute to the cognitive consequences of cancer treatment. Re- cent studies have pointed to endocrine disruptions, particularly in gonadal hormones, as a potential factor explaining cognitive difficulty [3,10,11]. Alter- ation in stress hormone metabolism, either as a result of cancer treatment or emotional distress resulting from cancer, has also been proposed to play a role [12]. Ovarian function is often dramatically altered by treatment for breast cancer, primarily because the use of various hormonal therapies, including GnRH agonists, aromatase inhibitors, and specific estrogen receptor modulators (SERMs). Several studies have indicated that the effects of treatment on ovarian func- tion play a role in determining cognitive outcomes. Women treated with both chemotherapy and the SERM Tamoxifen (AstraZeneca, London, UK) show greater cognitive impairment than those receiving che- motherapy alone [10]. Similarly, breast cancer patients who experience a treatment‐induced menopause are more likely to show cognitive symptoms than those who do not [13], and cognitive symptoms from che- motherapy are more frequently reported in younger, premenopausal women, for whom cancer treatment will induce a larger average hormonal change [14]. Studies that have separated treatments targeting the hypothalamic‐gonadal axis from other anticancer therapies have also indicated independent effects. Compared with healthy controls, premenopausal Copyright # 2011 John Wiley & Sons, Ltd. Psycho-Oncology Psycho-Oncology (2011) Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/pon.2006