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Letter to the Editor   |    
Estradiol Effects on the Postmenopausal Brain
EYDIE L. MOSES-KOLKO, M.D.; CAROLYN CIDIS MELTZER, M.D.; PHIL GREER, M.S.; MERYL BUTTERS, Ph.D.; SARAH L. BERGA, M.D.; GWENN SMITH, Ph.D.; WAYNE C. DREVETS, M.D.
Am J Psychiatry 2004;161:2136-2136. doi:10.1176/appi.ajp.161.11.2136

To the Editor: We commend Akira Kugaya, M.D., Ph.D., and colleagues (1) on their brief report on serotonin 2A (5-HT2A) receptors in postmenopausal women. Characterization of the effects of gonadal steroids on neuroreceptor pharmacology and cognitive function holds great importance to clinical care and cognitive neuroscience research. Consistent with the article by Dr. Kugaya et al., we previously reported that 5-HT2A receptor binding potential significantly increased in postmenopausal women during administration of transdermal estradiol, 0.1 mg/day for 8 to 14 weeks, followed by combined transdermal estradiol and progesterone, 100 mg b.i.d. (2 to 6 weeks), with positron emission tomography and the selective 5-HT2A receptor radioligand [18F]altanserin. Dr. Kugaya et al. correctly cited this publication as reporting a "subthreshold" effect of estradiol alone on increasing 5-HT2A receptor binding potential in specific brain regions of interest. However, we alert readers to our more recent publication (2), in which our original image data were analyzed voxel by voxel using statistical parametric mapping, a technique similar to that applied by Dr. Kugaya et al. Consistent with the work of Dr. Kugaya et al., this approach showed that administration of estradiol alone increased 5-HT2A receptor binding potential in multiple brain regions that had not been examined in our initial region-of-interest analysis (3), which included the right superior frontal gyrus, the right ventrolateral prefrontal cortex, the left inferior parietal cortex, and the left temporal polar cortex. Furthermore, in a post hoc analysis that employed a lower significance threshold for identifying voxels with increased 5-HT2A receptor binding potential after estradiol treatment (the same threshold used by Dr. Kugaya et al.), we observed widespread increases in estradiol-related cortical 5-HT2A receptor binding potential.

Given the clinical risks and benefits associated with the hormone replacement therapy regimens investigated in recent large-scale clinical trials (4, 5), mechanistic studies such as these may help shift the focus to alternate hormone replacement therapy regimens that may exert potentially beneficial effects on brain function. Both our study and that of Dr. Kugaya et al. lack the sensitivity needed to establish relationships between changes in 5-HT2A receptor binding and cognitive function or emotional behavior, which minimizes the potential for making clinical inferences. The sensitivity of both studies was limited by small group sizes and ceiling/floor effects on neuropsychological test performance in cognitively intact euthymic women. The findings of these studies nevertheless support the initiation and inform the design of future studies aimed at investigating neurobiological bases for the potential neuropsychiatric benefits of such treatments in specific patient populations.

Kugaya A, Epperson CN, Zoghbi S, van Dyck CH, Hou Y, Fujita M, Staley JK, Garg PK, Seibyl JP, Innis RB: Increase in prefrontal cortex serotonin2A receptors following estrogen treatment in postmenopausal women. Am J Psychiatry  2003; 160:1522–1524
[PubMed]
[CrossRef]
 
Moses-Kolko EL, Berga SL, Greer PJ, Smith G, Meltzer CC, Drevets WC: Widespread increases of cortical serotonin 2A (5HT2A) receptor availability following hormone replacement therapy in euthymic postmenopausal women. Fertil Steril  2003; 80:554–559
[PubMed]
[CrossRef]
 
Moses EL, Drevets WC, Smith G, Mathis CA, Kalro BN, Butters MA, Leondires MP, Greer PJ, Lopresti B, Loucks TL, Berga SL: Effects of estradiol and progesterone administration on human serotonin 2A receptor binding: a PET study. Biol Psychiatry  2000; 48:854–860
[PubMed]
[CrossRef]
 
Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA  2002; 288:321–333
[PubMed]
[CrossRef]
 
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jone BN, Assaf AR, Jackson RD, Kotchen JM, Waaertheil-Smoller S, Wactawski-Wende J: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study—a randomized controlled trial. JAMA  2003; 289:2651–2662
[PubMed]
[CrossRef]
 
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References

Kugaya A, Epperson CN, Zoghbi S, van Dyck CH, Hou Y, Fujita M, Staley JK, Garg PK, Seibyl JP, Innis RB: Increase in prefrontal cortex serotonin2A receptors following estrogen treatment in postmenopausal women. Am J Psychiatry  2003; 160:1522–1524
[PubMed]
[CrossRef]
 
Moses-Kolko EL, Berga SL, Greer PJ, Smith G, Meltzer CC, Drevets WC: Widespread increases of cortical serotonin 2A (5HT2A) receptor availability following hormone replacement therapy in euthymic postmenopausal women. Fertil Steril  2003; 80:554–559
[PubMed]
[CrossRef]
 
Moses EL, Drevets WC, Smith G, Mathis CA, Kalro BN, Butters MA, Leondires MP, Greer PJ, Lopresti B, Loucks TL, Berga SL: Effects of estradiol and progesterone administration on human serotonin 2A receptor binding: a PET study. Biol Psychiatry  2000; 48:854–860
[PubMed]
[CrossRef]
 
Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA  2002; 288:321–333
[PubMed]
[CrossRef]
 
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jone BN, Assaf AR, Jackson RD, Kotchen JM, Waaertheil-Smoller S, Wactawski-Wende J: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study—a randomized controlled trial. JAMA  2003; 289:2651–2662
[PubMed]
[CrossRef]
 
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