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- Bäckström, Torbjörn, et al.
(författare)
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Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons
- 2011
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Ingår i: Neuroscience. - Oxford : Elsevier BV. - 0306-4522 .- 1873-7544. ; 191:Special issue, s. 46-54
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Forskningsöversikt (refereegranskat)abstract
- Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane C1(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. (C) 2011 Published by Elsevier Ltd on behalf of IBRO.
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| 2. |
- Ekholm, Ulla-Britt, et al.
(författare)
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Sexuality and androgens in women with cyclical mood changes and pre-menstrual syndrome
- 2014
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 93:3, s. 248-255
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Tidskriftsartikel (refereegranskat)abstract
- Objective To study the relation between androgen levels and sexual interest in women with different kinds of pre-menstrual syndrome (PMS). Design Causal comparative study. Setting Swedish university hospital outpatient clinic. Population Seventy women with cyclical mood changes. Methods Pre-menstrual syndrome patients were divided into those with and those without preovulatory symptoms. In 37 women, early follicular phase blood samples were analyzed for androstenedione, testosterone, sex hormone-binding globulin (SHBG), progesterone and estradiol, using radioimmunoassay. The participants were divided into subgroups depending on whether the levels of androgens and SHBG were above or below the median. In 33 of them it was possible to compare the cyclicity in sexual parameters between these subgroups. Main outcome measures Daily ratings of sexual parameters and hormonal analyses. Results Plasma testosterone was significantly lower and SHBG significantly higher in women with luteal phase symptoms compared with those with additional follicular phase symptoms. ANOVA showed significant cyclicity for all sexual parameters consistently. For the “sexual feelings” and “pleasant sexual thoughts” parameters, cyclicity was the same whether or not the hormonal levels were “high” or “low.” Conclusions The “Pure-PMS” group and the “pre-menstrual-exacerbation” groups differed in their androgen and SHBG levels. Women suffering from PMS with higher neuroticism Eysenck Personality Inventory scores or “low” levels of androgens and SHBG would be more likely to have a decreased sexual interest pre-menstrually than would women with a high level.
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| 3. |
- Turkmen, Sahruh, et al.
(författare)
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Tolerance to allopregnanolone with focus on the GABA-A receptor
- 2011
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Ingår i: British Journal of Pharmacology. - : Wiley-Blackwell. - 0007-1188 .- 1476-5381. ; 162:2, s. 311-327
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Tidskriftsartikel (refereegranskat)abstract
- Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid -A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial (VPM) nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors.
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