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  • Print publication year: 2009
  • Online publication date: July 2010

Chapter 12 - Clinical data of estrogen's effects in the central nervous system: estrogen and mood

from Section 3 - Potential modulators and modifiers of estrogenic effects


Editors' introduction

In this chapter, Rasgon and colleagues first review the neurochemical basis underlying estrogen therapy use in mood disorders. They follow with an analysis of changes in estrogen and mood during different hormonal states associated with the menstrual cycle, birthing, and menopause. Results of their analysis indicate that a considerable body of basic science findings support the assertion that estrogens are prime regulators of the neurobiology of mood in women. However, there is discordance between results of animal and human studies. The source of disparity between the basic and clinical science outcomes remains undetermined but indicates the need for larger clinical trials and longitudinal studies that could identify women who are likely to respond well to estrogen monotherapy and estrogen augmentation to antidepressant treatments.


1. Stoppe G, Doren M. Critical appraisal of effects of estrogen replacement therapy on symptoms of depressed mood. Arch Women Ment Health. 2002;5(2):39–47.
2. Cone RI, Davis GA, Goy RW. Effects of ovarian steroids on serotonin metabolism within grossly dissected and microdissected brain regions of the ovariectomized rat. Brain Res Bull. 1981;7:639–44.
3. Biegnon A. Effects of steroid hormones on the serotonergic system. In Whitaker-Azmida PM, Peroutka SJ, eds. The Neuropharmacology of Serotonin. New York Academy of Sciences, 1990, pp. 427–31.
4. Sherwin BB, Suranyi-Cadotte BE. Up-regulatory effect of estrogen on platelet 3H-imipramine binding sites in surgically menopausal women. Biol Psychiatry. 1990;28(4):339–48.
5. Guicheney P, Leger D, Barrat J, et al. Platelet serotonin content and plasma tryptophan in peri- and postmenopausal women: variations with plasma oestrogen levels and depressive symptoms. Eur J Clin Invest. 1988;18(3):297–304.
6. Rehavi M, Sepcuti H, Weizman A. Upregulation of imipramine binding and serotonin uptake by estradiol in female rat brain. Brain Res. 1987;410:135–9.
7. McQueen JK, Wilson H, Fink G. Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain. Brain Res Mol Brain Res. 1997;45(1):13–23.
8. Moses-Kolko EL, Greer PJ, Smith G, et al. Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women. Fertil Steril. 2003;80:554–9.
9. Kuyaga A, Epperson N, Zoghbi S, et al. Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women. Am J Psych. 2003;160:1522–4.
10. Ball P, Knuppen R, Haupt M, Breuer H. Interactions between estrogens and catechol amines. 3. Studies on the methylation of catechol estrogens, catechol amines and other catechols by the catechol-O-methyltransferases of human liver. J Clin Endocrinol Metab. 1972;34(4):736–46.
11. Biegnon A, Reches A, Synder L, et al. Serotonergic and noradrenergic receptor in the rat brain: modulation by chronic exposure to ovarian hormones. Life Sci. 1983;32:2015–21.
12. Petrovic SI, McDonald JK, DeCastro G, et al. Regulation of anterior pituitary and brain beta-adrenergic receptors by ovarian steroids. Life Sci. 1983;37:1563–70.
13. Etgen AM, Karkanias GB. Estrogen regulation of noradrenergic signaling in the hypothalamus. Psychoneuroendocrinology. 1994;19(5/7):603–10.
14. Mamounas LA, Blue ME, Siuciak JA, et al. Estradiol-17β increases serotonin transporter (SERT) mRNA levels and the density of SERT-biding sites in female rat brain. Molecular Brain Res. 1997;45:13–23.
15. Mamounas LA, Altar CA, Blue ME, et al. BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci. 2000;20(2):771–82.
16. Siuciak JA, Clark MS, Rind HB, et al. BDNF induction of tryptophan hydroxylase mRNA levels in the rat brain. J Neurosci Res. 1998;52(2):149–58.
17. Cavus I, Duman RS. Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats. Biol Psychiatry. 2003;54(1):59–69.
18. Frank RT. Hormonal causes of premenstrual tension. Arch Neurol Psychiatry. 1931;26:1053–7.
19. Severino SK, Moline ML. Premenstrual Syndrome. A Clinicians Guide. New York: Guilford Press, 1989.
20. Watts JF, Butts WR, Edwards RI, et al. Hormonal studies in women with premenstrual tension. Br J Obstet Gynecol. 1985;92:247–55.
21. Rubinow DR, Hoban MC, Grover GN, 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.
22. Dennerstein L, Brown JB, Gotts G, et al. Menstrual cycle hormonal profiles of women with and without premenstrual syndrome. J Psychosom Obstet Gynecol. 1993;14:259–68.
23. Schmidt PJ, Nieman LK, Danaceau MA, et al. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338:209–16.
24. Hammarback S, Damber JF, Backstrom T. Relationship between symptom severity and hormone changes in women with premenstrual syndrome. J Clin Endocrinol Metab. 1989;68:125–30.
25. Dhar V, Murphy GE. Double blind randomized crossover trial of luteal phase estrogens (Premarin) in the premenstrual syndrome (PMS). Psychoneuroendocrinology. 1990;15:489–93.
26. Smith RN, Studd JW, Zamblera D, et al. A randomized comparison over 8 months of 100 micrograms and 200 micrograms twice weekly doses of transdermal oestradiol in the treatment of severe premenstrual syndrome. Br J Obstet Gynaecol. 1995;102(6):475–84.
27. Backstrom T, Hansson-Malmstrom Y, Lindhe BA, et al. Oral contraceptive in premenstrual syndrome: a randomized comparison of triphasic and monophasic preparations. Contraception. 1992;46(3):253–68.
28. Watson NR, Studd JW, Savvas M, et al. Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone. Lancet. 1989;23:730–2.
29. Rapkin AJ, Mikacich JA, Moatakef-Imani B, et al. The clinical nature and formal diagnosis of premenstrual, postpartum, and perimenopausal affective disorders. Curr Psychiatry Rep. 2002;4(6):419–28.
30. Freeman EW, Kroll R, Rapkin A, et al. Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder. J Womens Health Gend Based Med. 2001;20:561–96.
31. Pearlstein TB, Bachmann GA, Zacur HA, Yonkers KA. Treatment of premenstrual dysphoric disorder with a new drospirenone-containing oral contraceptive formulation. Contraception. 2005;72(6):414–21.
32. Yonkers KA, Brown C, Pearlstein TB, et al. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol. 2005;106:492–501.
33. Hendrick V, Altshuler L, Suri R. Hormonal chanages in the postpartum and implications for postpartum depression. Psychosomatics. 1998;39:93–101.
34. Bloch M, Schmidt PJ, Danaceau M, et al. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psych. 2000;157:924–30.
35. Galea LA, Wide JK, Alasdair MB. Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression. Behav Brain Res. 2001;122:1–9.
36. Ahokas A, Kaukoranta J, Wahlbeck K, Aito M. Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17beta-estradiol: a preliminary study. J Clin Psychiatry. 2001;62(5):332–6.
37. Gregoire AJP, Kumar R, Everitt B, et al. Transdermal oestrogen for treatment of severe postnatal depression. Lancet. 1996;347:930–3.
38. Soules MR, Sherman S, Parrott E et al. Stages of Reproductive Aging workshop (STRAW). J Womens Health Gend Based Med. 2001;10(9):843–8.
39. Steiner M, Dunn E, Born L. Hormones and mood: from menarche to menopause and beyond. J Affect Disord. 2003;74(1):67–83.
40. Judd HL. Transdermal estradiol. A potentially improved method of hormone replacement. J Reprod Med. 1994;39(5):343–52.
41. Nelson HD, Vesco KK, Haney E et al. Nonhormonal therapies for menopausal hot flashes systematic review and meta-analysis. JAMA. 2006;295:2057.
42. Schmidt PJ, Roca CA, Bloch M, et al. The perimenopause and affective disorders. Semin Reprod Endocrinol. 1997;15(1):91–100.
43. Banger M. Affective syndrome during perimenopause. Maturitas. 2002;41(Suppl 1):S13–8.
44. Novaes C, Almeida OP, de Melo NR. Mental health among perimenopausal women attending a menopause clinic: possible association with premenstrual syndrome? Climacteric. 1998;1(4):264–70.
45. Avis NE, Brambilla D, McKinlay SM, et al. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women's Health Study. Ann Epidemiol. 1994;4(3):214–20.
46. Freeman EW, Sammel MD, Liu L, Gracia, et al. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry. 2004;61(1):62–70.
47. Schmidt PJ, Haq N, Rubinow DR. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Am J Psychiatry. 2004;161(12):2238–44.
48. Harlow BL, Wise LA, Otto MW, et al. Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the Harvard Study of Moods and Cycles. Arch Gen Psychiatry. 2003;60(1):29–36.
49. Klaiber EL, Broverman DM, Vogel W, et al. Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry. 1979;36(5):550–4.
50. Amsterdam J, Garcia-Espana F, Fawcett J, et al. Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord. 1999;55(1):11–7.
51. Shapira B, Oppenheim G, Zohar J, et al. Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry. 1985;20(5):576–9.
52. Pearce J, Hawton K, Blake F. Psychological and sexual symptoms associated with the menopause and the effects of hormone replacement therapy. Br J Psychiatry. 1995;167(2):163–73.
53. Miller KJ. The other side of estrogen replacement therapy: outcome study results of mood improvement in estrogen users and nonusers. Curr Psychiatry Rep. 2003;5(6):439–44.
54. Zweifel JE, O'Brien WH. A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology. 1997;22(3):189–212. Erratum in: Psychoneuroendocrinology. 1997;22(8):655.
55. Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol. 2000;183(2):414–20.
56. Soares CN, Almeida OP, Joffe H, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry. 2001;58(6):529–34.
57. Canada SA, Hofkamp M, Gall EP, et al. Estrogen replacement therapy, subsyndromal depression, and orthostatic blood pressure regulation. Behav Med. 2003;29(3):101–6.
58. Cohen LS, Soares CN, Poitras JR, et al. Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Am J Psychiatry. 2003;160(8):1519–22.
59. Altshuler LL. The use of SSRIs in depressive disorders specific to women. J Clin Psychiatry. 2002;63(Suppl 7):3–8.
60. Halbreich U, Rojansky N, Palter S, et al. Estrogen augments serotonergic activity in postmenopausal women. Biol Psychiatry. 1995;37(7):434–41.
61. Grigoriadis S, Kennedy SH, Bagby RM. A comparison of antidepressant response in younger and older women. J Clin Psychopharmacol. 2003;23(4):405–7.
62. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445–52.
63. Oppenheim G. A case of rapid mood cycling with estrogen: implications for therapy. J Clin Psychiatry. 1984;45(1):34–5.
64. Young RC, Moline M, Kleyman F. Hormone replacement therapy and late-life mania. Am J Geriatr Psychiatry. 1997;5(2):179–81.
65. Schneider LS, Small GW, Hamilton SH, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group. Am J Geriatr Psychiatry. 1997;5(2):97–106.
66. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9(4):393–9.
67. Rasgon NL, Altshuler LL, Fairbanks LA, et al. Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. J Clin Psychiatry. 2002;63(Suppl 7):45–8.
68. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3/4):338–43.