Estrogens may affect the essential n-6 and n-3 fatty acids arachidonic acid (AA; C20:4n-6) and docosahexaenoic acid (DHA; C22:6n-3). Therefore, we investigated the long-term effects of hormone replacement therapy and raloxifene, a selective estrogen-receptor modulator, in two randomized, double-blind, placebo-controlled studies. In study I, 95 healthy, non-hysterectomized, early postmenopausal women (age range 47-59 years) received one of the following treatments: daily raloxifene 60 mg (n=24), daily raloxifene 150 mg (n=23), 0·625 mg conjugated equine estrogens (CEE) plus 2·5 mg medroxyprogesterone acetate (MPA; n=24), or placebo (n=24). In study II, 30 men (age range 60-69 years) received daily 120 mg raloxifene (n=15) or placebo (n=15). In study I, plasma cholesteryl ester fatty acids were measured at baseline and after 6, 12, and 24 months in 83 (drop out rate 13%), 73 (23%), and 70 (25%) women respectively. In study II, fatty acids were measured at baseline and after 3 months in 29 men (drop out rate 3%). In postmenopausal women, administration of 150 mg raloxifene increased AA by a mean of +6·1% (P=0·055, not significant). Administration of CEE plus MPA increased AA by +14·1% (P<0·0005). Mean changes in DHA were +22·1% (P=0·003) and +14·9% (P=0·047) respectively, as compared with placebo. In men, 120 mg raloxifene for 3 months did not significantly affect AA (-5·2%; P=0·342) or DHA (+4·0%; P=0·755), but it increased testosterone levels by +19·8% (P=0·006). Administration of raloxifene 150 mg/day as well as CEE plus MPA to postmenopausal women increases the proportion of AA and DHA in plasma cholesteryl esters during a follow-up of 2 years. Short term administration of raloxifene in elderly men did not affect AA or DHA. The synthesis of AA and DHA from precursors may be enhanced through an estrogen receptor-dependent pathway.

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Raloxifene is a selective estrogen receptor modulator that may delay the onset of mild cognitive impairment in elderly women. Effects of raloxifene treatment on mental performance in males remain to be investigated. In a previous functional magnetic resonance imaging (fMRI) study, we showed that raloxifene treatment enhanced brain activation in elderly males during encoding of new information (faces) into memory. The current study used fMRI in the same group of subjects to screen for effects of raloxifene treatment on brain function during face recognition. Healthy elderly males (n ¼ 28; mean age 63.6 years, SD 2.4) were scanned at baseline and after 3 months of treatment with either raloxifene 120 mg (n ¼ 14) or placebo (n ¼ 14) in a randomized, double-blind, placebo-controlled study design. Functional data were analyzed in an event-related fashion with respect to correct hits and correct rejections using FSL software. Performance data were analyzed with respect to recognition accuracy, latency, and response bias. Functional effects of treatment were found on brain activation related to correct hits only. When compared to placebo treatment, raloxifene treatment enhanced brain activation in the left posterior parahippocampal area (Z ¼ 3.9) and right inferior prefrontal cortex (Z ¼ 3.5). Recognition accuracy scores remained stable in the raloxifene group, whereas the placebo group showed a small but significant decrease in accuracy scores (p ¼ 0.02). No significant effects were found on response bias or latency. In conclusion, raloxifene treatment affects brain function during memory performance in a way that may reflect increased arousal during initial encoding, with downstream effects on brain function during retrieval of information. Behaviorally, such neurofunctional effects may actively block decreased memory performance as a result of contextdependency. The validity of these predictions can be tested in large-scale clinical trials.

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