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- Andréen, Lotta, 1961-
(författare)
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Allopregnanolone and mood : studies of postmenopausal women during treatment with progesterone
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction. Allopregnanolone and pregnanolone (neuroactive metabolites of progesterone) act as positive modulators of the GABAA receptor system which is the major inhibitory system in CNS. Contradictory results on the effect of GABAA receptor modulators are reported. Beneficial properties such as anaesthesia, sedation, and anxiolysis are reported as well as adverse, anxiogenic and aggressive effects. It has been suggested that GABAA receptor agonists have bimodal effects. Low concentrations increase an adverse, anxiogenic effect, whereas higher concentrations show beneficial, calming properties. Aims. To investigate if progesterone treatment induces adverse mood in postmenopausal women and if the severity in mood symptoms is related to progesterone, allopregnanolone or pregnanolone serum concentrations. To evaluate differences in steroid concentrations induced by different doses and routes of administration of progesterone. Methods. Two randomised, placebo-controlled, double-blind crossover studies of postmenopausal women were performed. Subjects were treated with estradiol continuously. Different doses of progesterone, given vaginally or orally, were added sequentially during the last 14 days of each treatment cycle. Daily symptom ratings were kept using a validated rating scale. Blood samples for progesterone, allopregnanolone and pregnanolone analyses were collected during each treatment cycle. A study regarding the pharmacokinetics after ingestion of low-dose oral progesterone was conducted with postmenopausal women. Blood samples for the analyses of progesterone, allopregnanolone and pregnanolone were collected and pharmacokinetic parameters were calculated. Results. Certain postmenopausal women on sequential HT with vaginal and oral progesterone experience mood deterioration during the progesterone phase while on a low dose of progesterone but not on higher doses or the placebo. Negative mood symptoms occurred when the serum concentration of allopregnanolone was similar to endogenous luteal phase levels, whereas lower and higher concentrations had no effect on mood. Pharmacokinetic analyses show that low-dose oral progesterone can be used as a prodrug to allopregnanolone when the aim is to achieve physiological concentrations of allopregnanolone. Conclusions. A bimodal association between allopregnanolone concentration and adverse mood is observed in postmenopausal women treated with progesterone. The addition of low-dose progesterone to estradiol induces adverse mood in postmenopausal women, whereas higher doses and placebo have no mood-deteriorating effect.
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| 5. |
- Andréen, Lotta, et al.
(författare)
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Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators
- 2009
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 34:8, s. 1121-1132
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Tidskriftsartikel (refereegranskat)abstract
- 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 GABA(A) system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABA(A) receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABA(A) 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 GABA(A) 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 GABA(A) receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABA(A) 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 GABA(A) receptor. CONCLUSION: Progesterone and progestagens induce negative mood, most probably via their GABA(A) 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.
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| 6. |
- Birzniece, Vita, et al.
(författare)
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GABA(A) receptor changes in acute allopregnanolone tolerance
- 2006
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 535:1-3, s. 125-134
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Tidskriftsartikel (refereegranskat)abstract
- To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.
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- Bäckström, Torbjörn, et al.
(författare)
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Isoallopregnanolone; an antagonist to the anaesthetic effect of allopregnanolone in male rats
- 2005
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Ingår i: European Journal of Pharmacology. - Amsterdam : North-Holland. - 0014-2999 .- 1879-0712. ; 512:1, s. 15-21
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Tidskriftsartikel (refereegranskat)abstract
- The interaction of isoallopregnanolone (3β-OH-5α-pregnan-20-one) on allopregnanolone (3α-OH-5α-pregnan-20-one) induced anaesthesia was studied in male rats using burst suppression of 1 s (“silent second”) with an electroencephalographic-threshold method. The i.v. administration of isoallopregnanolone was varied in relation to induction of “silent second”. Pre-treatment with isoallopregnanolone (12.5–50 mg/kg iv) 2 min prior to the threshold test gave an increase in the threshold dose of allopregnanolone(ANOVA df(3;36), F=13.61, P<0.001), which was dose dependent (r=0.73, b [slope]=0.08, df=38, P<0.001). After isoallopregnanolone pre-treatment, but not in the controls, anaesthesia time was positively related to the dose of allopregnanolone (r=0.52, b=1.72, df=28,P<0.01). Anaesthesia times were not influenced by a corresponding administration of isoallopregnanolone immediately after induction of “silent second”. When allopregnanolone and isoallopregnanolone were infused together at molar ratios of 1:1, 1:1.23, 1:1.43, a linear increase of the threshold doses of allopregnanolone was seen in relation to the dose of isoallopregnanolone (r=0.86, b=0.40, df=8,P<0.01). Thus isoallopregnanolone can antagonise the anaesthetic action of allopregnanolone.
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- Dennerstein, Lorraine, et al.
(författare)
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Premenstrual symptoms - severity, duration and typology : an international cross-sectional study
- 2009
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Ingår i: Menopause international. - : SAGE Publications. - 1754-0453. ; 15:3, s. 120-126
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Determine women's experiences of premenstrual symptoms. STUDY DESIGN: Cross-sectional survey. Sample In all, 4085 women aged 14-49 years recruited by random telephone digit dialing in France, Germany, Hungary, Italy, Spain, UK, Brazil and Mexico. Main outcome measures Telephone interview checklist of 23 premenstrual symptoms, sociodemographic variables and lifestyle variables. RESULTS: The most prevalent symptoms were abdominal bloating, cramps or abdominal pain, breast tenderness, irritability and mood swings. Severity of symptoms is directly proportional to duration (R = 0.79). Hierarchical clustering found the following mental and physical domains and a typology: 'Mild' type (40.8%) with minimal symptoms; 'Moderate M' type (28.7%) with moderately severe, mostly mental symptoms; 'Moderate P' type (21.9%) with moderately severe, mostly physical symptoms; and 'Severe' type (8.6%) with severe intensity of both mental and physical symptoms. Multiple stepwise regression found significant effects on symptom duration severity index of age (linear and quadratic effects), current smoking and country. CONCLUSIONS: Further research is needed on the impact of premenstrual symptoms on quality of life, and whether a brief symptom list could be developed as a valid and reliable tool globally.
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