Elsevier

Psychoneuroendocrinology

Volume 34, Issue 8, September 2009, Pages 1121-1132
Psychoneuroendocrinology

REVIEW
Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators

https://doi.org/10.1016/j.psyneuen.2009.02.003Get rights and content

Summary

Certain women experience negative mood symptoms as a result of progesterone during the luteal phase of the menstrual cycle, progestagens in hormonal contraceptives, or the addition of progesterone or progestagens in sequential hormone therapy (HT). This phenomenon is believed to be mediated via the action of the progesterone metabolites on the GABAA system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABAA receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABAA receptor modulators have shown contradictory results; although human and animal studies have revealed beneficial properties such as anaesthesia, sedation, anticonvulsant effects, and anxiolytic effects, recent reports have also indicated adverse effects such as anxiety, irritability, and aggression. It has actually been suggested that several GABAA receptor modulators, including allopregnanolone, have biphasic effects, in that low concentrations increase an adverse, anxiogenic effect whereas higher concentrations decrease this effect and show beneficial, calming properties.

The allopregnanolone increase during the luteal phase in fertile women, as well as during the addition of progesterone in HT, has been shown to induce adverse mood in women. The severity of these mood symptoms is related to the allopregnanolone serum concentrations in a manner similar to an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. It has also been shown that progesterone/allopregnanolone treatment in women increases the activity in the amygdala (as measured with functional magnetic resonance imaging) in a similar way to the changes seen during anxiety reactions. However, it is evident that only certain women experience adverse mood during progesterone or GABAA receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABAA receptor sensitivity and GABA concentrations that are related to the severity of the condition. These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABAA receptor.

Conclusion: Progesterone and progestagens induce negative mood, most probably via their GABAA receptor active metabolites. In postmenopausal women treated with progesterone and animals treated with allopregnanolone, there is a bimodal association between serum allopregnanolone concentration and adverse mood, resembling an inverted U-shaped curve. In humans, the maximal effective concentration of allopregnanolone for producing negative mood is within the range of physiological luteal phase serum concentrations.

Introduction

Mood disorders are a common health problem among women, especially during the reproductive years. Women are approximately twice as likely as men to report a lifetime history of major depression or anxiety disorder. Periods of hormonal variability, that is, menarche (Angold et al., 1999), premenstrual periods (Soares et al., 2001), postpartum (Chaudron et al., 2001), and perimenopause (Freeman et al., 2004) have been suggested to increase the risk of mood disorders in certain women. Therefore, it seems likely that sex steroid hormones can provide one possible explanation for the differences in mood disorders observed between the genders.

The sex steroid hormones act directly and indirectly via different neurotransmitter systems in the central nervous system (CNS). One of these systems is the gamma aminobutyric acid A (GABAA) receptor complex, which is the major inhibitory system in the mammalian CNS (Majewska et al., 1986). There is evidence for an interaction between mood effects and GABAA modulatory agents such as benzodiazepines, barbiturates, and alcohol. In addition, several neuroactive metabolites of steroid hormones, such as allopregnanolone and pregnanolone, are also modulators of the GABAA receptor complex; for this reason, they are known as GABA steroids. This review will therefore concentrate on arguments indicating a link between GABA steroids and negative mood effects.

In this context, GABA steroids are defined as steroids produced mainly by the ovary during the menstrual cycle, but also by the adrenals, and by the testes in men. The steroids are transported in the blood from the production unit to the brain. GABA steroids are also produced directly in the brain in both sexes (Celotti et al., 1992). Previous work by our group, among others, has shown that with the exception of oestradiol it is not the classic hormones that achieve many of the CNS effects. Instead, the 3alpha-hydroxy-5alpha/beta metabolites of progesterone (pregnanolone and allopregnanolone), testosterone (3alpha-5alpha-androstan-diol), and desoxycorticosterone (tetra-hydro-desoxycortico-sterone, THDOC) have a direct impact on the GABA system via the GABAA receptor (Majewska et al., 1986, Birzniece et al., 2006). These so-called GABA steroids modulate the brain's largest inhibiting system, the GABA system, by enhancing the effect on the GABAA receptor of GABA itself.

Section snippets

Sex steroid induced negative mood

Three obvious examples where there is evidence for the interaction between mood, steroids, and the CNS are: (i) premenstrual dysphoric disorder (PMDD), (ii) the negative mood symptoms encountered during sequential progestagen addition to oestrogen treatment in postmenopausal women, and (iii) the side effects of oral contraceptives (OCs).

The GABA paradox

It seems plausible to assume that all GABA allosteric modulators have similar behavioural as well as adverse effects. However, there is an obvious contradiction in the effects mediated by GABA active modulators. The positive effects, such as anxiolysis and sedation, are well known; but there is also evidence for the opposite, namely adverse effects, which also seem to be mediated by the GABAA receptor. This paradox of positive as well as adverse effects being mediated by GABA modulators is

GABA steroids and mood

With regard to GABA steroids, allopregnanolone has been found to be the most potent of the progesterone metabolites, followed by pregnanolone (Norberg et al., 1987, Paul and Purdy, 1992, Zhu et al., 2001, Timby et al., 2005). In fertile women, the circulating levels of allopregnanolone and pregnanolone follow that of progesterone, with higher concentrations during the luteal phase than in the follicular phase (Genazzani et al., 1998, Wang et al., 1996, Nyberg et al., 2007). A human post-mortem

A biphasic effect of GABAA modulators

In an attempt to explain the GABA paradox, it has been suggested that in certain individuals several GABAA receptor modulators, including allopregnanolone, have biphasic effects, with low doses or concentrations increasing an adverse, anxiogenic effect, and high doses or concentrations decreasing this effect and having more calming properties. The exact mechanism of this phenomenon is not known, but it is often referred to as a biphasic or bimodal effect. A hypothetical model of the biphasic

Potential mechanisms underlying the GABA-paradox

The results in the literature indicate two potential underlying mechanisms for the GABA-paradox; 1/disinhibition of output neurons or 2/reversal of Cl current at the α4β2δ GABAA receptor. One of these mechanisms alone could be a possible reason to why allopregnanolone induce adverse mood effects. The shown paradoxical increase in the activity of the amygdala might reflect the disinhibition of the principal neurons of the amygdala via inhibition of inhibitory interneurons. As was shown in fMRI

Conclusions

Why is it that GABAA receptor positive modulators, such as benzodiazepines, barbiturates, alcohol and allopregnanolone show paradoxical effects in some individuals, rather than being anxiolytic and calming? These positive modulators have the opposite effect and instead cause anxiety, depression, and irritability/aggression. Given these findings, it seems plausible to conclude that a subset of individuals is sensitive to low doses or concentrations of GABAA receptor modulators and thus respond

Role of funding source

The funding has been unrestricted research grants from local, national and international souses. No influence on the text has been performed.

Conflict of interest

In this paper there is no involvement of commercial partners or other factors that could cause a conflict of interest. The paper is based on 25 years of research in the field.

Acknowledgements

This work was supported by the Swedish Medical Research Council (proj. 4X-11198), Umeå sjukvård, spjutspetsanslag, Visare Norr Norra Regionen, and by a grant from the EU Regional Funds, Objective 1. The financial support is from research grants and sponsors had no influence on the studies or the text.

References (119)

  • D. Bitran et al.

    Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor

    Brain Res.

    (1991)
  • M. Bixo et al.

    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)
  • I. Bjorn et al.

    Drug related negative side-effects is a common reason for poor compliance in hormone replacement therapy

    Maturitas

    (1999)
  • I. Bjorn et al.

    Negative mood changes during hormone replacement therapy: a comparison between two progestogens

    Am. J. Obstet. Gynecol.

    (2000)
  • H. de Wit et al.

    Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women

    Psychoneuroendocrinology

    (2001)
  • H.A. Droogleever Fortuyn et al.

    Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density

    Psychoneuroendocrinology

    (2004)
  • P. Follesa et al.

    Changes in GABAA receptor gamma 2 subunit gene expression induced by long-term administration of oral contraceptives in rats

    Neuropharmacology

    (2002)
  • S.S. Girdler et al.

    Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder

    Biol. Psychiatry

    (2001)
  • J.W. Goldzieher

    Are low-dose oral contraceptives safer and better?

    Am. J. Obstet. Gynecol.

    (1994)
  • C. Gottesmann

    GABA mechanisms and sleep

    Neuroscience

    (2002)
  • M. Gulinello et al.

    Short-term exposure to a neuroactive steroid increases alpha4 GABA(A) receptor subunit levels in association with increased anxiety in the female rat

    Brain Res.

    (2001)
  • V.J. Honan

    Paradoxical reaction to midazolam and control with flumazenil

    Gastrointest. Endosc.

    (1994)
  • I.M. Johansson et al.

    Allopregnanolone inhibits learning in the Morris water maze

    Brain Res.

    (2002)
  • M. Kurthen et al.

    Severe negative emotional reactions in intracarotid sodium amytal procedures: further evidence for hemispheric asymmetries?

    Cortex

    (1991)
  • G. Larsson et al.

    A longitudinal study of birth control and pregnancy outcome among women in a Swedish population

    Contraception

    (1997)
  • M. Lofgren et al.

    Progesterone withdrawal effects in the open field test can be predicted by elevated plus maze performance

    Horm. Behav.

    (2006)
  • K.A. Miczek et al.

    Neurosteroids, GABAA receptors, and escalated aggressive behavior

    Horm. Behav.

    (2003)
  • S. Nyberg et al.

    Altered sensitivity to alcohol in the late luteal phase among patients with premenstrual dysphoric disorder

    Psychoneuroendocrinology

    (2004)
  • K.A. Oinonen et al.

    To what extent do oral contraceptives influence mood and affect?

    J. Affect. Disord.

    (2002)
  • X. Protopopescu et al.

    Toward a functional neuroanatomy of premenstrual dysphoric disorder

    J. Affect. Disord.

    (2008)
  • A.J. Rapkin et al.

    Progesterone metabolite allopregnanolone in women with premenstrual syndrome

    Obstet. Gynecol.

    (1997)
  • A.J. Rapkin et al.

    Decreased neuroactive steroids induced by combined oral contraceptive pills are not associated with mood changes

    Fertil. Steril.

    (2006)
  • S.A. Sanders et al.

    A prospective study of the effects of oral contraceptives on sexuality and well-being and their relationship to discontinuation

    Contraception

    (2001)
  • S.S. Smith et al.

    Neurosteroid regulation of GABA(A) receptors: focus on the alpha4 and delta subunits

    Pharmacol. Ther.

    (2007)
  • J. Stromberg et al.

    Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor

    Neuroscience

    (2006)
  • I. Sundstrom et al.

    Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: a pilot study

    Psychoneuroendocrinology

    (1997)
  • L. Andreen et al.

    Progesterone effects during sequential hormone replacement therapy

    Eur. J. Endocrinol.

    (2003)
  • L. Andreen et al.

    Allopregnanolone concentration and mood—a bimodal association in postmenopausal women treated with oral progesterone

    Psychopharmacology (Berl)

    (2006)
  • A. Angold et al.

    Pubertal changes in hormone levels and depression in girls

    Psychol. Med.

    (1999)
  • T. Backstrom et al.

    The role of hormones and hormonal treatments in premenstrual syndrome

    CNS Drugs.

    (2003)
  • T. Backstrom et al.

    Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy

    Acta Neurol. Scand.

    (1984)
  • J.C. Ballenger

    Overview of different pharmacotherapies for attaining remission in generalized anxiety disorder

    J. Clin. Psychiatry

    (2001)
  • D. Benke et al.

    GABAA receptors containing the α4-subunit: prevalence, distribution, pharmacology, and subunit architecture in situ

    J. Neurochem.

    (1997)
  • I. Bjorn et al.

    The impact of different doses of medroxyprogesterone acetate on mood symptoms in sequential hormonal therapy

    Gynecol. Endocrinol.

    (2002)
  • I. Bjorn et al.

    Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy

    J. Clin. Endocrinol. Metab.

    (2003)
  • P. Carl et al.

    Pregnanolone emulsion. A preliminary pharmacokinetic and pharmacodynamic study of a new intravenous anaesthetic agent

    Anaesthesia

    (1990)
  • F. Celotti et al.

    The 5 alpha-reductase in the brain: molecular aspects and relation to brain function

    Front. Neuroendocrinol.

    (1992)
  • A.F. Chan et al.

    Persistence of premenstrual syndrome during low-dose administration of the progesterone antagonist RU 486

    Obstet. Gynecol.

    (1994)
  • L.H. Chaudron et al.

    Predictors, prodromes and incidence of postpartum depression

    J. Psychosom. Obstet. Gynaecol.

    (2001)
  • D.R. Cherek et al.

    Effects of response requirement and alcohol on human aggressive responding

    J. Exp. Anal. Behav.

    (1992)
  • Cited by (0)

    View full text