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Effects of the experimental administration of oral estrogen on prefrontal functions in healthy young women

  • Tobias Sommer
  • Katharina Richter
  • Franziska Singer
  • Birgit Derntl
  • Gabriele M. Rune
  • Esther Diekhof
  • Janine Bayer
Original Investigation

Abstract

17-Beta-estradiol (E2) stimulates neural plasticity and dopaminergic transmission in the prefrontal cortex, which is critically involved in attentional control, working memory, and other executive functions. Studies investigating E2’s actions on prefrontally mediated behavior in the course of the menstrual cycle or during hormone replacement therapy are inconclusive, with numerous null findings as well as beneficial and detrimental effects. The current study focused on the effect of E2 on attentional performance, as animal studies indicate that supraphysiological doses (i.e., above estrous cycle levels) of E2 have beneficial effects on measures of attention in female rodents. To translate these findings to humans, we administered 12 mg E2-valerate or placebo orally to 34 naturally cycling women in the low-hormone early follicular phase using a randomized, double-blinded, pre-post design. Behavioral performance was tested twice during baseline and E2 peak, where E2 levels reached mildly supraphysiological levels in the E2 group. Aside from mainly prefrontally mediated tasks of attention, working memory, and other executive functions, we employed tasks of affectively modulated attention, emotion recognition, and verbal memory. E2 administration had a significant, but subtle negative impact on general processing speed and working memory performance. These effects could be related to an overstimulation of dopaminergic transmission. The negative effect of supraphysiological E2 on working memory connects well to animal literature. There were no effects on attentional performance or any other measure. This could be explained by different E2 levels being optimal for changing behavioral performance in specific tasks, which likely depends on the brain regions involved.

Keywords

Estrogen Prefrontal functions Attention Working memory Affectively modulated attention Verbal memory Emotion recognition 

Notes

Funding

The project was supported by a grant of the German Research Foundation (DFG SO 952/6-1), a grant of the state of Hamburg (UHH LFF FV 27), and the German Society for Psychosomatic Obstetrics and Gynecology (Deutsche Gesellschaft für Psychosomatische Frauenheilkunde und Geburtshilfe; DGPFG).

Compliance with ethical standards

Participants received financial compensation and gave written informed consent according to the Declaration of Helsinki. Ethics approval was obtained from the Ethics Committee of the Hamburg Medical Association (PV3612).

Conflict of interest

The authors declare that there is no conflict of interest.

Supplementary material

213_2018_5061_MOESM1_ESM.doc (126 kb)
ESM 1 (DOC 126 kb)

References

  1. Baayen RH, Davidson DJ, Bates DM (2008) Mixed-effects modeling with crossed random effects for subjects and items. J Mem Lang 59:390–412.  https://doi.org/10.1016/j.jml.2007.12.005 CrossRefGoogle Scholar
  2. Bäckman L, Ginovart N, Dixon RA, Wahlin TBR, Wahlin Å, Halldin C, Farde L (2000) Age-related cognitive deficits mediated by changes in the striatal dopamine system. AJP 157:635–637.  https://doi.org/10.1176/ajp.157.4.635 CrossRefGoogle Scholar
  3. Barnes P, Staal V, Muir J, Good MA (2006) 17-β estradiol administration attenuates deficits in sustained and divided attention in young ovariectomized rats and aged acyclic female rats. Behav Neurosci 120:1225–1234CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bates D, Maechler M, Bolker BM, Walker SC (2015) Fitting linear mixed-effects models using lme4. J Stat Softw 67:1–48CrossRefGoogle Scholar
  5. Bayer J, Gläscher J, Finsterbusch J, Schulte LH, Sommer T (2018) Linear and inverted U-shaped dose-response functions describe estrogen effects on hippocampal activity in young women. Nat Commun 9:1220.  https://doi.org/10.1038/s41467-018-03679-x CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bayer J, Rune G, Schultz H, Tobia MJ, Mebes I, Katzler O, Sommer T (2015) The effect of estrogen synthesis inhibition on hippocampal memory. Psychoneuroendocrinology 56:213–225.  https://doi.org/10.1016/j.psyneuen.2015.03.011 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bayer J, Schultz H, Gamer M, Sommer T (2014) Menstrual-cycle dependent fluctuations in ovarian hormones affect emotional memory. Neurobiol Learn Mem 110:55–63.  https://doi.org/10.1016/j.nlm.2014.01.017 CrossRefPubMedGoogle Scholar
  8. Bean LA, Ianov L, Foster TC (2014) Estrogen receptors, the hippocampus, and memory. Neuroscientist 20:534–545.  https://doi.org/10.1177/1073858413519865 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bohacek J, Daniel JM (2010) The beneficial effects of estradiol on attentional processes are dependent on timing of treatment initiation following ovariectomy in middle-aged rats. Psychoneuroendocrinology 35:694–705.  https://doi.org/10.1016/j.psyneuen.2009.10.010 CrossRefPubMedGoogle Scholar
  10. Brassen S, Gamer M, Büchel C (2011) Anterior cingulate activation is related to a positivity bias and emotional stability in successful aging. Biol Psychiatry 70:131–137.  https://doi.org/10.1016/j.biopsych.2010.10.013 CrossRefPubMedGoogle Scholar
  11. Bühner M, Schmidt-Atzert L, Richter S, Grieshaber E (2002) Selbstbeurteilungen der Aufmerksamkeit: Ein Vergleich zwischen Hirngeschädigten und Gesunden. Z Neuropsychol 13:263–269.  https://doi.org/10.1024//1016-264X.13.4.263 CrossRefGoogle Scholar
  12. Darne J, Mcgarrigle HHG, Lachelin GCL (1987) Saliva oestriol, oestradiol, oestrone and progesterone levels in pregnancy: spontaneous labour at term is preceded by a rise in the saliva oestriol:progesterone ratio. BJOG Int J Obstet Gynaecol 94:227–235.  https://doi.org/10.1111/j.1471-0528.1987.tb02359.x CrossRefGoogle Scholar
  13. Derntl B, Kryspin-Exner I, Fernbach E, Moser E, Habel U (2008) Emotion recognition accuracy in healthy young females is associated with cycle phase. Horm Behav 53:90–95.  https://doi.org/10.1016/j.yhbeh.2007.09.006 CrossRefPubMedGoogle Scholar
  14. Dresler T, Mériau K, Heekeren HR, van der Meer E (2009) Emotional Stroop task: effect of word arousal and subject anxiety on emotional interference. Psychol Res 73:364–371.  https://doi.org/10.1007/s00426-008-0154-6 CrossRefPubMedGoogle Scholar
  15. Duff SJ, Hampson E (2000) A beneficial effect of estrogen on working memory in postmenopausal women taking hormone replacement therapy. Horm Behav 38:262–276.  https://doi.org/10.1006/hbeh.2000.1625 CrossRefPubMedGoogle Scholar
  16. Edwards LJ, Muller KE, Wolfinger RD, et al (2008) An R2 statistic for fixed effects in the linear mixed model. Stat Med 27:6137–6157.  https://doi.org/10.1002/sim.3429 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Epperson CN, Amin Z, Ruparel K, Gur R, Loughead J (2012) Interactive effects of estrogen and serotonin on brain activation during working memory and affective processing in menopausal women. Psychoneuroendocrinology 37:372–382.  https://doi.org/10.1016/j.psyneuen.2011.07.007 CrossRefPubMedGoogle Scholar
  18. Finkel D, McArdle JJ, Reynolds CA et al (2009) Genetic variance in processing speed drives variation in aging of spatial and memory abilities. Dev Psychol 45:820–834.  https://doi.org/10.1037/a0015332 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Földényi M, Imhof K, Steinhausen HC (2000) Klinische Validität der computerunterstützten TAP bei Kindern mit Aufmerksamkeits-/Hyperaktivitätsstörungen. Z Neuropsychol 11:154–167CrossRefGoogle Scholar
  20. Frick KM, Kim J, Tuscher JJ, Fortress AM (2015) Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents. Learn Mem 22:472–493.  https://doi.org/10.1101/lm.037267.114 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Funahashi S (2017) Working memory in the prefrontal cortex. Brain Sci 7.  https://doi.org/10.3390/brainsci7050049 CrossRefPubMedCentralGoogle Scholar
  22. de Groot RHM, Hornstra G, Roozendaal N, Jolles J (2003) Memory performance, but not information processing speed, may be reduced during early pregnancy. J Clin Exp Neuropsychol 25:482–488.  https://doi.org/10.1076/jcen.25.4.482.13871 CrossRefPubMedGoogle Scholar
  23. Hampson E, Morley EE (2013) Estradiol concentrations and working memory performance in women of reproductive age. Psychoneuroendocrinology 38:2897–2904.  https://doi.org/10.1016/j.psyneuen.2013.07.020 CrossRefPubMedGoogle Scholar
  24. Hampson E, Phillips S-D, Duff-Canning SJ, Evans KL, Merrill M, Pinsonneault JK, Sadée W, Soares CN, Steiner M (2015) Working memory in pregnant women: relation to estrogen and antepartum depression. Horm Behav 74:218–227.  https://doi.org/10.1016/j.yhbeh.2015.07.006 CrossRefGoogle Scholar
  25. Han HJ, Lee K, Kim HT, Kim H (2014) Distinctive amygdala subregions involved in emotion-modulated Stroop interference. Soc Cogn Affect Neurosci 9:689–698.  https://doi.org/10.1093/scan/nst021 CrossRefPubMedGoogle Scholar
  26. Helmstaedter C, Lendt M, Lux S (2001) VLMT—Verbaler Lern- und Merkfähigkeitstest [Verbal Learning and Memory Test]. Hogrefe, GöttingenGoogle Scholar
  27. Hidalgo-Lopez E, Pletzer B (2017) Interactive effects of dopamine baseline levels and cycle phase on executive functions: the role of progesterone. Front Neurosci 11.  https://doi.org/10.3389/fnins.2017.00403
  28. Hogervorst E, Williams J, Budge M, Riedel W, Jolles J (2000) The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience 101:485–512CrossRefPubMedGoogle Scholar
  29. Holmes MM, Wide JK, Galea LAM (2002) Low levels of estradiol facilitate, whereas high levels of estradiol impair, working memory performance on the radial arm maze. Behav Neurosci 116:928–934CrossRefPubMedGoogle Scholar
  30. Jacobs E, D’Esposito M (2011) Estrogen shapes dopamine-dependent cognitive processes: implications for women’s health. J Neurosci 31:5286–5293.  https://doi.org/10.1523/JNEUROSCI.6394-10.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Jaeger B (2017) r2glmm: Computes R squared for mixed (Multilevel) models. R package version 0.1.2. https://www.CRAN.R-project.org/package=r2glmm. Accessed 01 Sept 2018
  32. Janowsky JS, Chavez B, Orwoll E (2000) Sex steroids modify working memory. J Cogn Neurosci 12:407–414.  https://doi.org/10.1162/089892900562228 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kampen DL, Sherwin BB (1994) Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 83:979–983CrossRefPubMedPubMedCentralGoogle Scholar
  34. Kane MJ, Engle RW (2002) The role of prefrontal cortex in working-memory capacity, executive attention, and general fluid intelligence: an individual-differences perspective. Psychon Bull Rev 9:637–671.  https://doi.org/10.3758/BF03196323 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Keenan PA, Ezzat WH, Ginsburg K, Moore GJ (2001) Prefrontal cortex as the site of estrogen’s effect on cognition. Psychoneuroendocrinology 26:577–590CrossRefPubMedPubMedCentralGoogle Scholar
  36. Kritzer MF, Kohama SG (1999) Ovarian hormones differentially influence immunoreactivity for dopamine β-hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys. J Comp Neurol 409:438–451.  https://doi.org/10.1002/(SICI)1096-9861(19990705)409:3<438::AID-CNE8>3.0.CO;2-5 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Krug R, Born J, Rasch B (2006) A 3-day estrogen treatment improves prefrontal cortex-dependent cognitive function in postmenopausal women. Psychoneuroendocrinology 31:965–975.  https://doi.org/10.1016/j.psyneuen.2006.05.007 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Leeners B, Kruger THC, Geraedts K, Tronci E, Mancini T, Ille F, Egli M, Röblitz S, Saleh L, Spanaus K, Schippert C, Zhang Y, Hengartner MP (2017) Lack of associations between female hormone levels and visuospatial working memory, divided attention and cognitive bias across two consecutive menstrual cycles. Front Behav Neurosci 11:120.  https://doi.org/10.3389/fnbeh.2017.00120 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Long NM, Öztekin I, Badre D (2010) Separable prefrontal cortex contributions to free recall. J Neurosci 30:10967–10976.  https://doi.org/10.1523/JNEUROSCI.2611-10.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Luders E, Gingnell M, Poromaa IS, Engman J, Kurth F, Gaser C (2018) Potential brain age reversal after pregnancy: younger brains at 4–6 weeks postpartum. Neuroscience 386:309–314.  https://doi.org/10.1016/j.neuroscience.2018.07.006 CrossRefPubMedGoogle Scholar
  41. Luine VN (2008) Sex steroids and cognitive function. J Neuroendocrinol 20:866–872.  https://doi.org/10.1111/j.1365-2826.2008.01710.x CrossRefPubMedGoogle Scholar
  42. Lundqvist D, Flykt A, Öhman A (1998) The Karolinska Directed Emotional Faces-KDEF. CD-ROM from Department of Clinical Neuroscience, Psychology section, Karolinska Institutet, Stockholm ISBN 91-630-7164-9Google Scholar
  43. Mannarelli D, Pauletti C, Grippo A, Amantini A, Augugliaro V, Currà A, Missori P, Locuratolo N, de Lucia MC, Rinalduzzi S, Fattapposta F (2015) The role of the right dorsolateral prefrontal cortex in phasic alertness: evidence from a contingent negative variation and repetitive transcranial magnetic stimulation study. Neural Plast 2015:1–9CrossRefGoogle Scholar
  44. McGaughy J, Sarter M (1999) Effects of ovariectomy, 192 IgG-saporin-induced cortical cholinergic deafferentation, and administration of estradiol on sustained attention performance in rats. Behav Neurosci 113:1216–1232CrossRefPubMedGoogle Scholar
  45. Mehta R, Kurmi N, Kaur M, Verma A (2017) Effect of pregnancy on the auditory and visual reaction time. Int J Res Med Sci 5:525–528.  https://doi.org/10.18203/2320-6012.ijrms20170144 CrossRefGoogle Scholar
  46. Ndefo UA, Mosely N (2010) Estradiol valerate and estradiol valerate/dienogest (natazia) tablets. P T 35:614–617PubMedPubMedCentralGoogle Scholar
  47. Nene AS, Pazare PA (2010) A study of auditory reaction time in different phases of the normal menstrual cycle. Indian J Physiol Pharmacol 54:386–390PubMedGoogle Scholar
  48. O’Leary P, Boyne P, Flett P et al (1991) Longitudinal assessment of changes in reproductive hormones during normal pregnancy. Clin Chem 37:667–672PubMedGoogle Scholar
  49. Olesen PJ, Westerberg H, Klingberg T (2004) Increased prefrontal and parietal activity after training of working memory. Nat Neurosci 7:75–79.  https://doi.org/10.1038/nn1165 CrossRefPubMedGoogle Scholar
  50. Pishnamazi M, Tafakhori A, Loloee S, Modabbernia A, Aghamollaii V, Bahrami B, Winston JS (2016) Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage. Cortex 81:24–34.  https://doi.org/10.1016/j.cortex.2016.04.012 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Portin R, Polo-Kantola P, Polo O, Koskinen T, Revonsuo A, Irjala K, Erkkola R (1999) Serum estrogen level, attention, memory and other cognitive functions in middle-aged women. Climacteric 2:115–123.  https://doi.org/10.3109/13697139909025575 CrossRefPubMedGoogle Scholar
  52. R Core Team (2014). R: A language and environment for statistical computing. R foundation for statistical computing. Vienna, Austria. https://www.R-project.org/. Accessed 15 June 2018
  53. Rosenberg L, Park S (2002) Verbal and spatial functions across the menstrual cycle in healthy young women. Psychoneuroendocrinology 27:835–841.  https://doi.org/10.1016/S0306-4530(01)00083-X CrossRefPubMedGoogle Scholar
  54. Rubia K, Smith AB, Brammer MJ, Taylor E (2003) Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection. NeuroImage 20:351–358.  https://doi.org/10.1016/S1053-8119(03)00275-1 CrossRefPubMedGoogle Scholar
  55. Schreckenberger M, Amberg R, Scheurich A, Lochmann M, Tichy W, Klega A, Siessmeier T, Gründer G, Buchholz HG, Landvogt C, Stauss J, Mann K, Bartenstein P, Urban R (2004) Acute alcohol effects on neuronal and attentional processing: striatal reward system and inhibitory sensory interactions under acute ethanol challenge. Neuropsychopharmacology 29:1527–1537.  https://doi.org/10.1038/sj.npp.1300453 CrossRefPubMedGoogle Scholar
  56. Shanmugan S, Epperson CN (2014) Estrogen and the prefrontal cortex: towards a new understanding of estrogen’s effects on executive functions in the menopause transition. Hum Brain Mapp 35:847–865.  https://doi.org/10.1002/hbm.22218 CrossRefPubMedGoogle Scholar
  57. Smith YR, Bowen L, Love TM, Berent-Spillson A, Frey KA, Persad CC, Reame NK, Koeppe RA, Zubieta JK (2011) Early initiation of hormone therapy in menopausal women is associated with increased hippocampal and posterior cingulate cholinergic activity. J Clin Endocrinol Metab 96:E1761–E1770.  https://doi.org/10.1210/jc.2011-0351 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Solís-Ortiz S, Corsi-Cabrera M (2008) Sustained attention is favored by progesterone during early luteal phase and visuo-spatial memory by estrogens during ovulatory phase in young women. Psychoneuroendocrinology 33:989–998.  https://doi.org/10.1016/j.psyneuen.2008.04.003 CrossRefPubMedGoogle Scholar
  59. Steyer R, Schwenkmezger P, Notz P, Eid M (1994) Testtheoretische Analysen des Mehrdimensionalen Befindlichkeitsfragebogen (MDBF). Diagnostica 40(4):320–328Google Scholar
  60. Sundström Poromaa I, Gingnell M (2014) Menstrual cycle influence on cognitive function and emotion processing—from a reproductive perspective. Front Neurosci 8:380.  https://doi.org/10.3389/fnins.2014.00380 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Symonds CS, Gallagher P, Thompson JM, Young AH (2004) Effects of the menstrual cycle on mood, neurocognitive and neuroendocrine function in healthy premenopausal women. Psychol Med 34:93–102.  https://doi.org/10.1017/S0033291703008535 CrossRefPubMedGoogle Scholar
  62. Tabachnick BG, Fidell LS (2014) Using multivariate statistics, 6th edn. Pearson Education, HarlowGoogle Scholar
  63. Turken U, Whitfield-Gabrieli S, Bammer R, Baldo JV, Dronkers NF, Gabrieli JDE (2008) Cognitive processing speed and the structure of white matter pathways: convergent evidence from normal variation and lesion studies. NeuroImage 42:1032–1044.  https://doi.org/10.1016/j.neuroimage.2008.03.057 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Twisk J, Bosman L, Hoekstra T et al (2018) Different ways to estimate treatment effects in randomised controlled trials. Contemp Clin Trials Commun 10:80–85CrossRefGoogle Scholar
  65. Van Breukelen GJP (2006) ANCOVA versus change from baseline: more power in randomized studies, more bias in nonrandomized studies [corrected]. J Clin Epidemiol 59:920–925.  https://doi.org/10.1016/j.jclinepi.2006.02.007 CrossRefPubMedGoogle Scholar
  66. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AFT (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10:376–384.  https://doi.org/10.1038/nn1846 CrossRefPubMedGoogle Scholar
  67. Võ ML, Conrad M, Kuchinke L et al (2009) The Berlin affective word list reloaded (BAWL-R). Behav Res Methods 41:534–538CrossRefPubMedGoogle Scholar
  68. Walf AA, Frye CA (2006) A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior. Neuropsychopharmacology 31:1097–1111CrossRefPubMedPubMedCentralGoogle Scholar
  69. Wide JK, Hanratty K, Ting J, Galea LAM (2004) High level estradiol impairs and low level estradiol facilitates non-spatial working memory. Behav Brain Res 155:45–53.  https://doi.org/10.1016/j.bbr.2004.04.001 CrossRefPubMedGoogle Scholar
  70. Willuhn I, Steiner H (2008) Motor-skill learning in a novel running-wheel task is dependent on D1 dopamine receptors in the striatum. Neuroscience 153:249–258.  https://doi.org/10.1016/j.neuroscience.2008.01.041 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Woolley CS, McEwen BS (1993) Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol 336:293–306.  https://doi.org/10.1002/cne.903360210 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Zhang S, Paul J, Nantha-Aree M, Buckley N, Shahzad U, Cheng J, DeBeer J, Winemaker M, Wismer D, Punthakee D, Avram V, Thabane L (2014) Empirical comparison of four baseline covariate adjustment methods in analysis of continuous outcomes in randomized controlled trials. Clin Epidemiol 6:227–235.  https://doi.org/10.2147/CLEP.S56554 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Zimmermann P, Fimm B (2002) A test battery for attentional performance. In: Applied neuropsychology of attention. Theory, diagnosis and rehabilitation. Psychology Press, London, pp 110–151Google Scholar
  74. Zimmermann P, Fimm B (2009) Testbatterie zur Aufmerksamkeitsprüfung-Version 2.2:(TAP);[Handbuch]. PsytestGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Systems NeuroscienceUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Department of Psychiatry and PsychotherapyUniversity Medical Center TübingenTübingenGermany
  3. 3.Department of NeuroanatomyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  4. 4.Department of Human Biology, Biocenter Grindel and Zoological InstituteHamburg UniversityHamburgGermany

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