Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Progesterone selectively increases amygdala reactivity in women

Abstract

The acute neural effects of progesterone are mediated by its neuroactive metabolites allopregnanolone and pregnanolone. These neurosteroids potentiate the inhibitory actions of γ-aminobutyric acid (GABA). Progesterone is known to produce anxiolytic effects in animals, but recent animal studies suggest that pregnanolone increases anxiety after a period of low allopregnanolone concentration. This effect is potentially mediated by the amygdala and related to the negative mood symptoms in humans that are observed during increased allopregnanolone levels. Therefore, we investigated with functional magnetic resonance imaging (MRI) whether a single progesterone administration to healthy young women in their follicular phase modulates the amygdala response to salient, biologically relevant stimuli. The progesterone administration increased the plasma concentrations of progesterone and allopregnanolone to levels that are reached during the luteal phase and early pregnancy. The imaging results show that progesterone selectively increased amygdala reactivity. Furthermore, functional connectivity analyses indicate that progesterone modulated functional coupling of the amygdala with distant brain regions. These results reveal a neural mechanism by which progesterone may mediate adverse effects on anxiety and mood.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Steiner M, Dunn E, Born L . Hormones and mood: from menarche to menopause and beyond. J Affect Disord 2003; 74: 67–83.

    Article  CAS  PubMed  Google Scholar 

  2. Kimura D . Sex and Cognition. The MIT Press: Cambridge, 1999.

    Book  Google Scholar 

  3. Sharp K, Brindle PM, Brown MW, Turner GM . Memory loss during pregnancy. Br J Obstet Gynaecol 1993; 100: 209–215.

    Article  CAS  PubMed  Google Scholar 

  4. Keenan PA, Yaldoo DT, Stress ME, Fuerst DR, Ginsburg KA . Explicit memory in pregnant women. Am J Obstet Gynecol 1998; 179: 731–737.

    Article  CAS  PubMed  Google Scholar 

  5. Buckwalter JG, Stanczyk FZ, McCleary CA, Bluestein BW, Buckwalter DK, Rankin KP et al. Pregnancy, the postpartum, and steroid hormones: effects on cognition and mood. Psychoneuroendocrinology 1999; 24: 69–84.

    Article  CAS  PubMed  Google Scholar 

  6. Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR . Prevalence of depression during pregnancy: systematic review. Obstet Gynecol 2004; 103: 698–709.

    Article  PubMed  Google Scholar 

  7. Bäckström T, Sanders D, Leask R, Davidson D, Warner P, Bancroft J . Mood, sexuality, hormones, and the menstrual cycle. II. Hormone levels and their relationship to the premenstrual syndrome. Psychosom Med 1983; 45: 503–507.

    Article  PubMed  Google Scholar 

  8. Rubinow DR, Hoban MC, Grover GN, Galloway DS, Roy-Byrne P, Andersen R et al. Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorder and in control subjects. Am J Obstet Gynecol 1988; 158: 5–11.

    Article  CAS  PubMed  Google Scholar 

  9. Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR . Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med 1998; 338: 209–216.

    Article  CAS  PubMed  Google Scholar 

  10. Rubinow DR, Schmidt PJ . Gonadal steroid regulation of mood: the lessons of premenstrual syndrome. Front Neuroendocrinol 2006; 27: 210–216.

    Article  CAS  PubMed  Google Scholar 

  11. Bitran D, Shiekh M, Mcleod M . Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain Gaba(a) receptors. J Neuroendocrinol 1995; 7: 171–177.

    Article  CAS  PubMed  Google Scholar 

  12. Smith SS, Gong QH, Hsu FC, Markowitz RS, ffrench-Mullen JM, Li X . GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 1998; 392: 926–930.

    Article  CAS  PubMed  Google Scholar 

  13. Reddy DS, O'Malley BW, Rogawski MA . Anxiolytic activity of progesterone in progesterone receptor knockout mice. Neuropharmacology 2005; 48: 14–24.

    Article  CAS  PubMed  Google Scholar 

  14. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM . Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986; 232: 1004–1007.

    Article  CAS  PubMed  Google Scholar 

  15. Akwa Y, Purdy RH, Koob GF, Britton KT . The amygdala mediates the anxiolytic-like effect of the neurosteroid allopregnanolone in rat. Behav Brain Res 1999; 106: 119–125.

    Article  CAS  PubMed  Google Scholar 

  16. Paul SM, Purdy RH . Neuroactive steroids. FASEB J 1992; 6: 2311–2322.

    Article  CAS  PubMed  Google Scholar 

  17. Zhu D, Wang MD, Bäckström T, Wahlström G . Evaluation and comparison of the pharmacokinetic and pharmacodynamic properties of allopregnanolone and pregnanolone at induction of anaesthesia in the male rat. Br J Anaesth 2001; 86: 403–412.

    Article  CAS  PubMed  Google Scholar 

  18. Smith SS, Ruderman Y, Frye C, Homanics G, Yuan M . Steroid withdrawal in the mouse results in anxiogenic effects of 3alpha,5beta-THP: a possible model of premenstrual dysphoric disorder. Psychopharmacology (Berl) 2006; 186: 323–333.

    Article  CAS  Google Scholar 

  19. Wang M, Seippel L, Purdy RH, Backstrom T . Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one. J Clin Endocrinol Metab 1996; 81: 1076–1082.

    CAS  PubMed  Google Scholar 

  20. Davis M, Whalen PJ . The amygdala: vigilance and emotion. Mol Psychiatry 2001; 6: 13–34.

    Article  CAS  PubMed  Google Scholar 

  21. Phillips ML, Drevets WC, Rauch SL, Lane R . Neurobiology of emotion perception I: the neural basis of normal emotion perception. Biol Psychiatry 2003; 54: 504–514.

    Article  PubMed  Google Scholar 

  22. de Lignieres B, Dennerstein L, Backstrom T . Influence of route of administration on progesterone metabolism. Maturitas 1995; 21: 251–257.

    Article  CAS  PubMed  Google Scholar 

  23. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E et al. The mini-international neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59(Suppl 20): 22–33.

    PubMed  Google Scholar 

  24. Bond A, Lader M . The use of analogue scales in rating subjective feelings. Br J Med Psychol 1974; 47: 211–218.

    Article  Google Scholar 

  25. Spielberger CD, Gorsuch RL, Lushene RE . STAI Manual for the State Trait Anxiety Inventory. Consulting Psychologists Press: Palo Alto, 1970.

    Google Scholar 

  26. Hariri AR, Mattay VS, Tessitore A, Fera F, Smith WG, Weinberger DR . Dextroamphetamine modulates the response of the human amygdala. Neuropsychopharmacology 2002; 27: 1036–1040.

    Article  CAS  PubMed  Google Scholar 

  27. Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB . Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch Gen Psychiatry 2005; 62: 282–288.

    Article  CAS  PubMed  Google Scholar 

  28. Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frackowiak RSJ . Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 2: 189–210.

    Article  Google Scholar 

  29. Friston KJ, Penny W, Phillips C, Kiebel S, Hinton G, Ashburner J . Classical and Bayesian inference in neuroimaging: theory. Neuroimage 2002; 16: 465–483.

    Article  CAS  PubMed  Google Scholar 

  30. Friston KJ, Buechel C, Fink GR, Morris J, Rolls E, Dolan RJ . Psychophysiological and modulatory interactions in neuroimaging. Neuroimage 1997; 6: 218–229.

    Article  CAS  PubMed  Google Scholar 

  31. Worsley KJ, Marrett S, Neelin P, Vandal AC, Friston KJ, Evans AC . A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp 1996; 4: 58–73.

    Article  CAS  PubMed  Google Scholar 

  32. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH . An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003; 19: 1233–1239.

    Article  PubMed  Google Scholar 

  33. Kanwisher N, McDermott J, Chun MM . The fusiform face area: a module in human extrastriate cortex specialized for face perception. J Neurosci 1997; 17: 4302–4311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brett M, Anton J, Valbregue R, Poline J . Region of interest analysis using an SPM toolbox (abstract). 8th International Conference on Functional Mapping of the Human Brain, 2–6 June 2002; Sendai, Japan, 2002, p 497.

  35. Andréen L, Sundström-Poromaa I, Bixo M, Andersson A, Nyberg S, Bäckström T . Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone. Psychoneuroendocrinology 2005; 30: 212–224.

    Article  PubMed  Google Scholar 

  36. Parizek A, Hill M, Kancheva R, Havlikova H, Kancheva L, Cindr J et al. Neuroactive pregnanolone isomers during pregnancy. J Clin Endocrinol Metab 2005; 90: 395–403.

    Article  CAS  PubMed  Google Scholar 

  37. Paoletti AM, Romagnino S, Contu R, Orru MM, Marotto MF, Zedda P et al. Observational study on the stability of the psychological status during normal pregnancy and increased blood levels of neuroactive steroids with GABA-A receptor agonist activity. Psychoneuroendocrinology 2006; 31: 485–492.

    Article  CAS  PubMed  Google Scholar 

  38. Phelps EA, LeDoux JE . Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 2005; 48: 175–187.

    Article  CAS  PubMed  Google Scholar 

  39. Rauch SL, Shin LM, Wright CI . Neuroimaging studies of amygdala function in anxiety disorders. Ann N Y Acad Sci 2003; 985: 389–410.

    Article  PubMed  Google Scholar 

  40. Drevets WC . Neuroimaging abnormalities in the amygdala in mood disorders. Ann N Y Acad Sci 2003; 985: 420–444.

    Article  PubMed  Google Scholar 

  41. Tsao DY, Freiwald WA, Tootell RB, Livingstone MS . A cortical region consisting entirely of face-selective cells. Science 2006; 311: 670–674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Amaral DG, Behniea H, Kelly JL . Topographic organization of projections from the amygdala to the visual cortex in the macaque monkey. Neuroscience 2003; 118: 1099–1120.

    Article  CAS  PubMed  Google Scholar 

  43. Vuilleumier P, Richardson MP, Armony JL, Driver J, Dolan RJ . Distant influences of amygdala lesion on visual cortical activation during emotional face processing. Nat Neurosci 2004; 7: 1271–1278.

    Article  CAS  PubMed  Google Scholar 

  44. Hariri AR, Mattay VS, Tessitore A, Fera F, Weinberger DR . Neocortical modulation of the amygdala response to fearful stimuli. Biol Psychiatry 2003; 53: 494–501.

    Article  PubMed  Google Scholar 

  45. Ochsner KN, Gross JJ . The cognitive control of emotion. Trends Cogn Sci 2005; 9: 242–249.

    Article  PubMed  Google Scholar 

  46. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 2005; 8: 828–834.

    Article  CAS  PubMed  Google Scholar 

  47. Bäckström T, Andersson A, Andree L, Birzniece V, Bixo M, Bjorn I et al. Pathogenesis in menstrual cycle-linked CNS disorders. Ann N Y Acad Sci 2003; 1007: 42–53.

    Article  PubMed  Google Scholar 

  48. Miczek KA, Fish EW, De Bold JF . Neurosteroids, GABAA receptors, and escalated aggressive behavior. Horm Behav 2003; 44: 242–257.

    Article  CAS  PubMed  Google Scholar 

  49. N-Wihlbäck AC, Sundström-Poromaa I, Bäckström T . Action by and sensitivity to neuroactive steroids in menstrual cycle related CNS disorders. Psychopharmacology (Berl) 2006; 186: 388–401.

    Article  Google Scholar 

  50. Fish EW, Faccidomo S, DeBold JF, Miczek KA . Alcohol, allopregnanolone and aggression in mice. Psychopharmacology (Berl) 2001; 153: 473–483.

    Article  CAS  Google Scholar 

  51. Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T . Allopregnanolone concentration and mood-a bimodal association in postmenopausal women treated with oral progesterone. Psychopharmacology (Berl) 2006; 187: 209–221.

    Article  Google Scholar 

  52. Freeman EW, Frye CA, Rickels K, Martin PA, Smith SS . Allopregnanolone levels and symptom improvement in severe premenstrual syndrome. J Clin Psychopharmacol 2002; 22: 516–520.

    Article  CAS  PubMed  Google Scholar 

  53. Timby E, Balgard M, Nyberg S, Spigset O, Andersson A, Porankiewicz-Asplund J et al. Pharmacokinetic and behavioral effects of allopregnanolone in healthy women. Psychopharmacology (Berl) 2006; 186: 414–424.

    Article  CAS  Google Scholar 

  54. Sundström I, Andersson A, Nyberg S, Ashbrook D, Purdy RH, Bäckström T . Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects. Neuroendocrinology 1998; 67: 126–138.

    Article  PubMed  Google Scholar 

  55. Hammarbäck S, Damber JE, Bäckström T . Relationship between symptom severity and hormone changes in women with premenstrual syndrome. J Clin Endocrinol Metab 1989; 68: 125–130.

    Article  PubMed  Google Scholar 

  56. Björn I, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström G, Bäckström T . Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy. J Clin Endocrinol Metab 2003; 88: 2026–2030.

    Article  PubMed  Google Scholar 

  57. Marowsky A, Yanagawa Y, Obata K, Vogt KE . A specialized subclass of interneurons mediates dopaminergic facilitation of amygdala function. Neuron 2005; 48: 1025–1037.

    Article  CAS  PubMed  Google Scholar 

  58. Belelli D, Herd MB, Mitchell EA, Peden DR, Vardy AW, Gentet L et al. Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance. Neuroscience 2006; 138: 821–829.

    Article  CAS  PubMed  Google Scholar 

  59. Shen H, Gong QH, Aoki C, Yuan M, Ruderman Y, Dattilo M et al. Reversal of neurosteroid effects at alpha4beta2delta GABA(A) receptors triggers anxiety at puberty. Nat Neurosci 2007; 10: 469–477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Price JL . Comparative aspects of amygdala connectivity. Ann N Y Acad Sci 2003; 985: 50–58.

    Article  PubMed  Google Scholar 

  61. Phillips ML, Drevets WC, Rauch SL, Lane R . Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 2003; 54: 515–528.

    Article  PubMed  Google Scholar 

  62. Fernández G, Weis S, Stoffel-Wagner B, Tendolkar I, Reuber M, Beyenburg S et al. Menstrual cycle-dependent neural plasticity in the adult human brain is hormone, task, and region specific. J Neurosci 2003; 23: 3790–3795.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Goldstein JM, Jerram M, Poldrack R, Ahern T, Kennedy DN, Seidman LJ et al. Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. J Neurosci 2005; 25: 9309–9316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Protopopescu X, Pan H, Altemus M, Tuescher O, Polanecsky M, McEwen B et al. Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle. Proc Natl Acad Sci USA 2005; 102: 16060–16065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Amin Z, Epperson CN, Constable RT, Canli T . Effects of estrogen variation on neural correlates of emotional response inhibition. Neuroimage 2006; 32: 457–464.

    Article  PubMed  Google Scholar 

  66. Adolphs R . How do we know the minds of others? Domain-specificity, simulation, and enactive social cognition. Brain Res 2006; 1079: 25–35.

    Article  CAS  PubMed  Google Scholar 

  67. Herman JP, Ostrander MM, Mueller NK, Figueiredo H . Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1201–1213.

    Article  CAS  PubMed  Google Scholar 

  68. Penton-Voak IS, Perrett DI, Castles DL, Kobayashi T, Burt DM, Murray LK et al. Menstrual cycle alters face preference. Nature 1999; 399: 741–742.

    Article  CAS  PubMed  Google Scholar 

  69. Jones BC, Little AC, Boothroyd L, Debruine LM, Feinberg DR, Smith MJ et al. Commitment to relationships and preferences for femininity and apparent health in faces are strongest on days of the menstrual cycle when progesterone level is high. Horm Behav 2005; 48: 283–290.

    Article  CAS  PubMed  Google Scholar 

  70. Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH . Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med 1999; 61: 154–162.

    Article  CAS  PubMed  Google Scholar 

  71. Roca CA, Schmidt PJ, Altemus M, Deuster P, Danaceau MA, Putnam K et al. Differential menstrual cycle regulation of hypothalamic-pituitary-adrenal axis in women with premenstrual syndrome and controls. J Clin Endocrinol Metab 2003; 88: 3057–3063.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by an internal grant from the Radboud University Nijmegen Medical Center, an EU structural fund objective 1 program, and the Swedish Research Council project 11198.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G A van Wingen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Wingen, G., van Broekhoven, F., Verkes, R. et al. Progesterone selectively increases amygdala reactivity in women. Mol Psychiatry 13, 325–333 (2008). https://doi.org/10.1038/sj.mp.4002030

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4002030

Keywords

This article is cited by

Search

Quick links