Skip to main content
SpringerLink
Log in

GABAA Receptor-Modulating Steroids in Relation to Women’s Behavioral Health

  • Women's Mental Health (CN Epperson, Section Editor)
  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

In certain women, increased negative mood relates to the progesterone metabolite, allopregnanolone (allo), during the luteal phase of ovulatory menstrual cycles, the premenstrual dysphoric disorder (PMDD). In anovulatory cycles, no symptom or sex steroid increase occurs but symptoms return during progesterone/allo treatment. Allo is a potent GABAA receptor-modulating steroid and as such is expected to be calming and anxiolytic. A relation to negative mood is unexpected. However, this paradoxical effect can be induced by all GABAA receptor modulators in low concentrations whereas higher concentrations are calming. The severity of the mood symptoms relate to allo in an inverted U-shaped curve at endogenous luteal-phase serum concentrations. Allo’s effects on the GABAA receptor can be antagonized by isoallopregnanolone (ISO), an antagonist to allo. ISO has also been used in a preliminary clinical trial on PMDD ameliorating symptoms with good effect in PMDD patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Nyberg S, Backstrom T, Zingmark E, Purdy RH, Poromaa IS. Allopregnanolone decrease with symptom improvement during placebo and gonadotropin-releasing hormone agonist treatment in women with severe premenstrual syndrome. Gynecol Endocrinol. 2007;23(5):257–66.

    Article  CAS  PubMed  Google Scholar 

  2. Innala E, Backstrom T, Poromaa IS, Andersson C, Bixo M. Women with acute intermittent porphyria have a defect in 5alpha-steroid production during the menstrual cycle. Acta Obstet Gynecol Scand. 2012;91(12):1445–52.

  3. Ottander U, Poromaa IS, Bjurulf E, Skytt A, Bäckström T, Olofsson JI. Allopregnanolone and pregnanolone are produced by the human corpus luteum. Mol Cell Endocrinol. 2005;239(1-2):37–44.

  4. American Psychiatric Association D-, Diagnostic and statistical manual of mental disorders (DSM-5). 2013: American Psychiatric Publishing.

  5. ACOG American College of Obstetricians and Gynecologists, ACOG practice bulletin. Premenstrual syndrome. nternational Journal of Gynecology & Obstetrics. 2001;73:183-–191.

    Google Scholar 

  6. Nevatte T, O’Brien PMS, Backstrom T, Brown C, Dennerstein L, Endicott J, et al. ISPMD consensus on the management of premenstrual disorders. Arch Womens Ment Health. 2013;16(4):279–91.

  7. Sundstrom Poromaa I, Gingnell M. Menstrual cycle influence on cognitive function and emotion processing-from a reproductive perspective. Front Neurosci. 2014;8:380.

    PubMed Central  PubMed  Google Scholar 

  8. Backstrom 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(6):503–7. This shows that symptoms are closely related to the allopregnanolone concentrations in serum.

  9. Backstrom T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, et al. Allopregnanolone and mood disorders. Prog Neurobiol. 2014;113:88–94.

  10. Hammarback S, Backstrom T. Induced anovulation as treatment of premenstrual tension syndrome. A double-blind cross-over study with GnRH-agonist versus placebo. Acta Obstet Gynecol Scand. 1988;67(2):159–66.

    Article  CAS  PubMed  Google Scholar 

  11. Hammarback S, Ekholm UB, Backstrom T. Spontaneous anovulation causing disappearance of cyclical symptoms in women with the premenstrual syndrome. Acta Endocrinol (Copenh). 1991;125(2):132–7. This shows that cyclocal symptoms in PMDD disappears in anovulatory cycles when allopregnanolone is not formed.

  12. Mortola JF, Girton L, Fischer U. Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin. J Clin Endocrinol Metab. 1991;72(2):252A–F.

    Article  CAS  PubMed  Google Scholar 

  13. Bixo M, Andersson A, Winblad B, Purdy RH, Backstrom T. Progesterone, 5alpha-pregnane-3,20-dione and 3alpha-hydroxy-5alpha-pregnane-20-one in specific regions of the human female brain in different endocrine states. Brain Res. 1997;764(1-2):173–8.

    Article  CAS  PubMed  Google Scholar 

  14. 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(4):209–16.

    Article  CAS  PubMed  Google Scholar 

  15. Segebladh B, Borgstrom A, Nyberg S, Bixo M, Sundstrom-Poromaa I. Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing hormone agonist treatment in patients with premenstrual dysphoric disorder. Am J Obstet Gynecol. 2009;201(2)):139–e1-8.

  16. Andreen L, Sundstrom-Poromaa I, Bixo M, Nyberg S, Backstrom T. Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone. Psychoneuroendocrinology. 2005;30(2):212–24.

  17. Andreen L, Sundstrom-Poromaa I, Bixo M, Andersson A, Nyberg S, Backstrom T. Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone. Psychopharmacology (Berl). 2006;187(2):209–21. PMDD like symptoms appear when postmenopausal women are treated with progesterone/allopregnanolone as HRT indicating that it is progesterone/allopregnanolone that causes the symptoms.

  18. Bjorn I, Sundstrom-Poromaa I, Bixo M, Nyberg S, Backstrom G, Backstrom T. Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy. J Clin Endocrinol Metab. 2003;88(5):2026–30.

  19. Dhar V, Murphy BE. Double-blind randomized crossover trial of luteal phase estrogens (Premarin) in the premenstrual syndrome (PMS). Psychoneuroendocrinology. 1990;15(5-6):489–93.

  20. Bjorn I, Bixo M, Nojd KS, Collberg P, Nyberg S, Sundstrom-Poromaa I, Backstrom T. The impact of different doses of medroxyprogesterone acetate on mood symptoms in sequential hormonal therapy. Gynecol Endocrinol. 2002;16(1):1–8.

  21. Hall RC, Zisook S. Paradoxical reactions to benzodiazepines. Br J Clin Pharmacol. 1981;11 Suppl 1:99S–04S.

    PubMed Central  PubMed  Google Scholar 

  22. Honan VJ. Paradoxical reaction to midazolam and control with flumazenil. Gastrointest Endosc. 1994;40(1):86–8.

    Article  CAS  PubMed  Google Scholar 

  23. Ben-Porath DD, Taylor SP. The effects of diazepam (valium) and aggressive disposition on human aggression: an experimental investigation. Addict Behav. 2002;27(2):167–77.

    Article  PubMed  Google Scholar 

  24. Masia SL, Perrine K, Westbrook L, Alper K, Devinsky O. Emotional outbursts and post-traumatic stress disorder during intracarotid amobarbital procedure. Neurology. 2000;54(8):1691–3.

  25. Weinbroum AA, Szold O, Ogorek D, Flaishon R. The midazolam-induced paradox phenomenon is reversible by flumazenil. Epidemiology, patient characteristics and review of the literature. Eur J Anaesthesiol. 2001;18(12):789–97.

  26. Sveindottir H, Backstrom T. Prevalence of menstrual cycle symptom cyclicity and premenstrual dysphoric disorder in a random sample of women using and not using oral contraceptives. Acta Obstet Gynecol Scand. 2000;79(5):405–13.

    Article  CAS  PubMed  Google Scholar 

  27. Kurthen M, Linke DB, Reuter BM, Hufnagel A, Elger CE. Severe negative emotional reactions in intracarotid sodium amytal procedures: further evidence for hemispheric asymmetries? Cortex. 1991;27(2):333–7.

    Article  CAS  PubMed  Google Scholar 

  28. Lee GP, Loring DW, Meador KJ, Flanigin HF, Brooks BS. Severe behavioral complications following intracarotid sodium amobarbital injection: implications for hemispheric asymmetry of emotion. Neurology. 1988;38(8):1233–6.

  29. Cherek DR, Spiga R, Egli M. Effects of response requirement and alcohol on human aggressive responding. J Exp Anal Behav. 1992;58(3):577–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Dougherty DM, Cherek DR, Bennett RH. The effects of alcohol on the aggressive responding of women. J Stud Alcohol. 1996;57(2):178–86.

    Article  CAS  PubMed  Google Scholar 

  31. Cullberg J. Mood changes and menstrual symptoms with different gestagen/estrogen combinations. A double blind comparison with placebo. Acta Psychiat Scand, 1972; 236(Suppl.):1-84

  32. Miczek KA, Fish EW, De Bold JF. Neurosteroids, GABAA receptors, and escalated aggressive behavior. Horm Behav. 2003;44(3):242–57.

    Article  CAS  PubMed  Google Scholar 

  33. Gourley SL, Debold JF, Yin W, Cook J, Miczek KA. Benzodiazepines and heightened aggressive behavior in rats: reduction by GABA(A)/alpha(1) receptor antagonists. Psychopharmacol (Berl). 2005;178(2-3):232–40.

  34. Weerts EM, Tornatzky W, Miczek KA. “Anxiolytic” and “anxiogenic” benzodiazepines and beta-carbolines: effects on aggressive and social behavior in rats and squirrel monkeys. Psychopharmacol (Berl). 1993;110(4):451–9.

    Article  CAS  Google Scholar 

  35. Andreen L, Spigset O, Andersson A, Nyberg S, Backstrom T. Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone. Maturitas. 2006;54(3):238–44.

    Article  CAS  PubMed  Google Scholar 

  36. van Wingen GA, van Broekhoven F, Verkes RJ, Petersson KM, Backstrom T, Buitelaar JK, et al. Progesterone selectively increases amygdala reactivity in women. Mol Psychiatry. 2008;13(3):325–33. This shows the paradoxical effect of progesterone/allopregnanolone on amygdala response to aversive pictures.

  37. 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(3):282–8.

  38. van Wingen G, van Broekhoven F, Verkes RJ, Petersson KM, Backstrom T, Buitelaar J, et al. How progesterone impairs memory for biologically salient stimuli in healthy young women. J Neurosci. 2007;27(42):11416–23. This shows the paradoxical effect of progesterone/allopregnanolone on amygdala response to aversive pictures.

  39. 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(1):395–403.

  40. Toffoletto S, Lanzenberger R, Gingnell M, Sundstrom-Poromaa I, Comasco E. Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: a systematic review. Psychoneuroendocrinology. 2014;50:28–52.

  41. Backstrom 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.

  42. Gingnell M, Ahlstedt V, Bannbers E, Wikstrom J, Sundstrom-Poromaa I, Fredrikson M. Social stimulation and corticolimbic reactivity in premenstrual dysphoric disorder: a preliminary study. Biol Mood Anxiety Disord. 2014;4(1):3.

  43. Protopopescu X, Tuescher O, Pan H, Epstein J, Root J, Chang L, et al. Toward a functional neuroanatomy of premenstrual dysphoric disorder. J Affect Disord. 2008;108(1-2):87–94.

  44. Sundstrom I, Nyberg S, Backstrom T. Patients with premenstrual syndrome have reduced sensitivity to midazolam compared to control subjects. Neuropsychopharmacology. 1997;17(6):370–81.

    Article  CAS  PubMed  Google Scholar 

  45. Sundstrom I, Ashbrook D, Backstrom T. Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: a pilot study. Psychoneuroendocrinology. 1997;22(1):25–38.

    Article  CAS  PubMed  Google Scholar 

  46. Nyberg S, Wahlstrom G, Backstrom T, Sundstrom Poromaa I. Altered sensitivity to alcohol in the late luteal phase among patients with premenstrual dysphoric disorder. Psychoneuroendocrinology. 2004;29(6):767–77.

  47. Sundstrom I, Andersson A, Nyberg S, Ashbrook D, Purdy RH, Backstrom T. Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects. Neuroendocrinology. 1998;67(2):126–38.

  48. Lundgren P, Stromberg J, Backstrom T, Wang M. Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3beta-hydroxy-5alpha-pregnan-20-one (isoallopregnanolone). Brain Res. 2003;982(1):45–53.

    Article  CAS  PubMed  Google Scholar 

  49. Wang MD, Backstrom T, Landgren S. The inhibitory effects of allopregnanolone and pregnanolone on the population spike, evoked in the rat hippocampal CA1 stratum pyramidale in vitro, can be blocked selectively by epiallopregnanolone. Acta Physiol Scand. 2000;169(4):333–41.

    Article  CAS  PubMed  Google Scholar 

  50. Backstrom T, Wahlstrom G, Wahlstrom K, Zhu D, Wang MD. Isoallopregnanolone; an antagonist to the anaesthetic effect of allopregnanolone in male rats. Eur J Pharmacol. 2005;512(1):15–21.

  51. Bengtsson SK, Nyberg S, Hedstrom H, Zingmark E, Jonsson B, Backstrom T, et al. Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans. Psychoneuroendocrinology. 2015;52:22–31. This shows that the effect of allopregnanolone on sedation and saccadic eye velocity can be inhibited by isoallopregnanolone.

  52. Bixo M. Biomarkers for premenstrual dysphoric disorder. GABAA modulating steroid antagonists -a possible treatment for premenstrual dysphoric disorder. . in 44th Annual Meeting of the International Society of Psychoneuroendocrinology, 19th-22nd August. 2014. Montreal, Canada.

  53. Stromberg J, Haage D, Taube M, Backstrom T, Lundgren P. Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor. Neuroscience. 2006;143(1):73–81.

  54. Havlikova H, Hill M, Kancheva L, Vrbikova J, Pouzar V, Cerny I, et al. Serum profiles of free and conjugated neuroactive pregnanolone isomers in nonpregnant women of fertile age. J Clin Endocrinol Metab. 2006;91(8):3092–9.

  55. Murphy BE, Abbott FV, Allison CM, Watts C, Ghadirian AM. Elevated levels of some neuroactive progesterone metabolites, particularly isopregnanolone, in women with chronic fatigue syndrome. Psychoneuroendocrinology. 2004;29(2):245–68.

  56. Romeo E, Strohle A, Spalletta G, di Michele F, Hermann B, Holsboer F, et al. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry. 1998;155(7):910–3.

  57. Cheney DL, Uzunov D, Costa E, Guidotti A. Gas chromatographic-mass fragmentographic quantitation of 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats. J Neurosci. 1995;15(6):4641–50.

    CAS  PubMed  Google Scholar 

  58. Puia G, Mienville JM, Matsumoto K, Takahata H, Watanabe H, Costa E, et al. On the putative physiological role of allopregnanolone on GABA(A) receptor function. Neuropharmacology. 2003;44(1):49–55.

  59. Holmberg E, Backstrom T, Johansson M, Lofgren M, Haage D. Allopregnanolone induces a diurnally dependent hyperphagic effect and alters feeding latency and duration in male Wistar rats. Acta Physiol (Oxf). 2013;208(4):400–9.

  60. Moller AT, Backstrom T, Nyberg S, Sondergaard HP, Helstrom L. Women with PTSD have a changed sensitivity to GABA-A receptor active substances. Psychopharmacology (Berl). 2014.

  61. Bertone-Johnson ER, Whitcomb BW, Missmer SA, Manson JE, Hankinson SE, Rich-Edwards JW. Early life emotional, physical, and sexual abuse and the development of premenstrual syndrome: a longitudinal study. J Womens Health (Larchmt). 2014;23(9):729–39.

  62. Breslau N, Chilcoat HD, Kessler RC, Davis GC. Previous exposure to trauma and PTSD effects of subsequent trauma: results from the Detroit Area Survey of Trauma. Am J Psychiatry. 1999;156(6):902–7.

  63. Roy-Byrne PP, Cowley DS, Greenblatt DJ, Shader RI, Hommer D. Reduced benzodiazepine sensitivity in panic disorder. Arch Gen Psychiatry. 1990;47(6):534–8.

Download references

Acknowledgments

The work that led to this review was supported by grants from the Swedish Research Council, medicine proj. 4X-11198, Västerbottensl läns landsting centrala ALF and spjutspets, Umecrine Mood AB, and Umeå University foundations.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Torbjörn Bäckström is a share holder in Umecrine AB.

Marie Bixo has nothing to declare.

Jessica Strömberg has nothing to declare.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Clinical sciences, Obstetrics and Gynecology, Umeå neurosteroid research center, Umeå University, Building 6M 4th floor, Umeå, Sweden

    Torbjörn Bäckström, Marie Bixo & Jessica Strömberg

Authors
  1. Torbjörn Bäckström
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marie Bixo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jessica Strömberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Torbjörn Bäckström.

Additional information

This article is part of the Topical Collection on Women’s Mental Health

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bäckström, T., Bixo, M. & Strömberg, J. GABAA Receptor-Modulating Steroids in Relation to Women’s Behavioral Health. Curr Psychiatry Rep 17, 92 (2015). https://doi.org/10.1007/s11920-015-0627-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11920-015-0627-4

Keywords

Search

Navigation