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Bixo, Marie
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Publications (10 of 48) Show all publications
Turkmen, S., Bixo, M., Hedström, H., Gideonsson, I., Nyberg, S., Wang, M. & Bäckström, T. (2016). The author's reply: Blood allopregnanolone levels in women with polycystic ovary syndrome [Letter to the editor]. Clinical Endocrinology, 85(1), 152-154.
Open this publication in new window or tab >>The author's reply: Blood allopregnanolone levels in women with polycystic ovary syndrome
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2016 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 85, no 1, 152-154 p.Article in journal, Letter (Refereed) Published
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-124215 (URN)10.1111/cen.13079 (DOI)000378512100023 ()27061597 (PubMedID)
Available from: 2016-08-01 Created: 2016-07-28 Last updated: 2017-11-28Bibliographically approved
Timby, E., Bäckström, T., Nyberg, S., Stenlund, H., Wihlbäck, A.-C. N. & Bixo, M. (2016). Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls — a pilot study. Psychopharmacology, 233(11), 2109-2117.
Open this publication in new window or tab >>Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls — a pilot study
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2016 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 11, 2109-2117 p.Article in journal (Refereed) Published
Abstract [en]

In premenstrual dysphoric disorder (PMDD), a condition that afflicts 3-8 % of women in fertile ages, the cyclic recurrence of debilitating mood symptoms is restricted to the luteal phase of the menstrual cycle. The progesterone metabolite allopregnanolone is produced by the corpus luteum, and circulating levels are reflected in the brain. Allopregnanolone is a modulator of the GABA(A) receptor, enhancing the effect of gamma-aminobutyric acid (GABA). Previous studies have demonstrated different sensitivity to other GABA(A) receptor agonists, i.e., benzodiazepines, alcohol, and pregnanolone, in PMDD patients compared to controls.

This study aimed to investigate the sensitivity to intravenous allopregnanolone over the menstrual cycle in PMDD patients.

Allopregnanolone, 0.05 mg/kg, was administered intravenously once in the mid-follicular and once in the luteal phase of the menstrual cycle to 10 PMDD patients and 10 control subjects. The saccadic eye velocity (SEV) was recorded by electrooculography as a measurement of functional GABA(A) receptor activity, at baseline and repeatedly after the injection. A mixed model was used to analyze data.

There was a highly significant group x phase interaction in the SEV response to allopregnanolone (F(1,327.489) = 12.747, p < 0.001). In the PMDD group, the SEV response was decreased in the follicular phase compared to the luteal phase (F(1,168) = 7.776, p = 0.006), whereas in the control group, the difference was opposite during the menstrual cycle (F(1,158.45) = 5.70, p = 0.018).

The effect of exogenous allopregnanolone is associated with menstrual cycle phase in PMDD patients and in controls. The results suggest an altered sensitivity to allopregnanolone in PMDD patients.

Keyword
Neurosteroid, GABA, Premenstrual dysphoric disorder, Saccadic eye velocity, Menstrual cycle
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-50057 (URN)10.1007/s00213-016-4258-1 (DOI)000376102100009 ()
Note

Originally included in thesis in manuscript form

Available from: 2011-11-24 Created: 2011-11-24 Last updated: 2017-12-08Bibliographically approved
Bäckström, T., Bixo, M. & Strömberg, J. (2015). GABAA Receptor-Modulating Steroids in Relation to Women’s Behavioral Health. Current Psychiatry Reports, 17(11), Article ID 92.
Open this publication in new window or tab >>GABAA Receptor-Modulating Steroids in Relation to Women’s Behavioral Health
2015 (English)In: Current Psychiatry Reports, ISSN 1523-3812, E-ISSN 1535-1645, Vol. 17, no 11, 92Article, review/survey (Refereed) Published
Abstract [en]

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 GABA(A) 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 GABA(A) 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 GABA(A) 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.

Keyword
GABA(A) receptor-modulating steroids, Premenstrual dysphoric disorder, Mood symptoms
National Category
Psychiatry
Identifiers
urn:nbn:se:umu:diva-110501 (URN)10.1007/s11920-015-0627-4 (DOI)000361741100007 ()26396092 (PubMedID)
Available from: 2016-01-15 Created: 2015-10-22 Last updated: 2017-11-30Bibliographically approved
Bengtsson, S. K. S., Nyberg, S., Hedström, H., Zingmark, E., Jonsson, B., Bäckström, T. & Bixo, M. (2015). Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans. Psychoneuroendocrinology, 52, 22-31.
Open this publication in new window or tab >>Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans
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2015 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 52, 22-31 p.Article in journal (Refereed) Published
Abstract [en]

Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of gamma-amino-butyric acid (GABA) on the GABA type A (GABA(A)) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABA(A) receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP-induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner.

Keyword
Allopregnanolone, Isoallopregnanolone, Saccadic eye velocity, GABA(A) receptor, Sedation, Premenstrual dysphoric disorder
National Category
Endocrinology and Diabetes Neurosciences
Identifiers
urn:nbn:se:umu:diva-100765 (URN)10.1016/j.psyneuen.2014.10.025 (DOI)000349271000004 ()25459890 (PubMedID)
Available from: 2015-04-26 Created: 2015-03-09 Last updated: 2018-01-11Bibliographically approved
Hedström, H., Bäckström, T., Bixo, M., Nyberg, S., Wang, M., Gideonsson, I. & Turkmen, S. (2015). Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA A receptor sensitivity to allopregnanolone. Clinical Endocrinology, 83(5), 643-650.
Open this publication in new window or tab >>Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA A receptor sensitivity to allopregnanolone
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2015 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 5, 643-650 p.Article in journal (Refereed) Published
Abstract [en]

ObjectiveSeveral studies have reported that -aminobutyric acid (GABA) ergic circuits are involved in the pathophysiology of polycystic ovary syndrome (PCOS). The progesterone metabolite allopregnanolone is a potent GABA(A)-receptor-modulating steroid, and patients may have increased concentrations of allopregnanolone or altered GABA(A) receptor sensitivity. We investigated both of these possibilities in this study. PatientsWe enrolled 9 women with PCOS and 24 age-matched eumenorrhoeic controls, who were divided into two groups by body mass index (BMI) (16 normal weight and 8 overweight). MeasurementsWe investigated the effects of allopregnanolone injection on GABA(A) receptor sensitivity in both groups of women. All women received a single intravenous dose of allopregnanolone (0050mg/kg). GABA(A) receptor sensitivity was assessed with the saccadic eye velocity (SEV) over 30 degrees (SEV30 degrees), the SEV30 degrees/allopregnanolone concentration ([Allo]) ratio, and sedation, which were measured together with serum allopregnanolone at intervals for 180min after injection. The controls were tested in the follicular phase of the menstrual cycle. ResultsBaseline allopregnanolone concentrations were higher in the PCOS women than in the normal-weight (P=0034) and overweight controls (P=0004). The allopregnanolone concentrations after injection were higher in the PCOS women (P=0006) and overweight controls (P=0037) than in the normal-weight controls. All groups showed a decline in the SEV30 degrees/[Allo] ratio after injection. Allopregnanolone had a smaller effect on the SEV30 degrees/[Allo] ratio in the overweight women (PCOS, P=0032; controls, P=0007) than in the normal-weight controls. The sedation score after allopregnanolone injection was lower in the PCOS patients than in the controls, but was not different between the two control groups. ConclusionsPCOS women had elevated baseline allopregnanolone concentrations compared with follicular-phase controls. All overweight women (PCOS and controls) were less sensitive to allopregnanolone than normal-weight controls.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-111462 (URN)10.1111/cen.12809 (DOI)000363267400008 ()25929428 (PubMedID)
Available from: 2015-12-01 Created: 2015-11-13 Last updated: 2017-12-01Bibliographically approved
Bixo, M. & Lindén Hirschberg, A. (2015). Ännu inte visat att östradiol och »naturligt« progesteron är säkert. Läkartidningen, 112(11), Article ID DAXW.
Open this publication in new window or tab >>Ännu inte visat att östradiol och »naturligt« progesteron är säkert
2015 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, no 11, DAXWArticle in journal (Refereed) Published
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-118525 (URN)25647107 (PubMedID)
Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2017-11-30Bibliographically approved
Bäckström, T., Bixo, M., Johansson, M., Nyberg, S., Ossewaarde, L., Ragagnin, G., . . . van Wingen, G. (2014). Allopregnanolone and mood disorders. Progress in Neurobiology, 113, 88-94.
Open this publication in new window or tab >>Allopregnanolone and mood disorders
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2014 (English)In: Progress in Neurobiology, ISSN 0301-0082, E-ISSN 1873-5118, Vol. 113, 88-94 p.Article in journal (Refereed) Published
Abstract [en]

Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in 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. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone. Conclusion: 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.

(c) 2013 Elsevier Ltd. All rights reserved.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-87179 (URN)10.1016/j.pneurobio.2013.07.005 (DOI)000331508100007 ()
Available from: 2014-03-31 Created: 2014-03-24 Last updated: 2017-12-05Bibliographically approved
Segebladh, B., Bannbers, E., Moby, L., Nyberg, S., Bixo, M., Bäckström, T. & Poromaa, I. S. (2013). Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder. Archives of Women's Mental Health, 16(2), 131-137.
Open this publication in new window or tab >>Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder
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2013 (English)In: Archives of Women's Mental Health, ISSN 1434-1816, E-ISSN 1435-1102, Vol. 16, no 2, 131-137 p.Article in journal (Refereed) Published
Abstract [en]

Most prior studies in patients with premenstrual dysphoric disorder (PMDD) indicate a blunted hypothalamus-pituitary-adrenal axis function. However, the relationship between neuroactive progesterone metabolites, such as allopregnanolone, and hypothalamus-pituitary-adrenal (HPA) axis function in PMDD patients is relatively sparsely studied. The primary aims of this study were to assess diurnal variation in circulating cortisol and low-dose dexamethasone suppression in PMDD patients and healthy controls, and the relationship between these two HPA axis indices and allopregnanolone serum concentrations. Twenty-six women with prospectively defined PMDD and 30 healthy controls were recruited. Participants underwent diurnal sampling for cortisol serum concentrations and a low-dose dexamethasone suppression test. In addition, morning allopregnanolone serum concentrations were determined. There was no difference in diurnal secretion of cortisol and degree of dexamethasone suppression of cortisol between PMDD patients and healthy controls. However, PMDD patients with high allopregnanolone levels displayed blunted nocturnal cortisol levels in comparison with healthy controls who had low allopregnanolone serum concentrations. In women with PMDD, diurnal secretion of cortisol may be influenced by allopregnanolone levels of the luteal phase. This finding may be attributed to timing of blood sampling in the late luteal phase as well as the individual level of allopregnanolone but could potentially explain the discrepancies in results between studies examining HPA axis function in women with PMDD.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-68252 (URN)10.1007/s00737-013-0327-1 (DOI)000316146300007 ()
Available from: 2013-04-18 Created: 2013-04-15 Last updated: 2017-12-06Bibliographically approved
Bäckström, T., Bixo, M., Nyberg, S. & Savic, I. (2013). Increased neurosteroid sensitivity - An explanation to symptoms associated with chronic work related stress in women?. Psychoneuroendocrinology, 38(7), 1078-1089.
Open this publication in new window or tab >>Increased neurosteroid sensitivity - An explanation to symptoms associated with chronic work related stress in women?
2013 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 7, 1078-1089 p.Article in journal (Refereed) Published
Abstract [en]

Work related psychosocial stress can be accompanied by so called burnout syndrome with symptoms of mental exhaustion, physical fatigue, and cognitive dysfunction. Underlying mechanisms for acquiring burnout syndrome are not clear. Animal studies show that chronic stress is associated with altered release of GABA-A receptor modulating steroids (GAMS), altered composition of the GABA-A receptor and altered sensitivity to GAMS. In the present study we investigated if such changes occur in women with burnout syndrome. We further asked whether flumazenil (a benzodiazepine antagonist, but with positive modulating effects on GABA-A receptors with altered subunit composition) can block the effect of the GAMS allopregnanolone. Ten women with occupational psychosocial stress and burnout syndrome were compared with twelve healthy controls in an experimental setting. Saccadic eye velocity (SEV) was measured after an injection of allopregnanolone, followed by an injection of flumazenil and a second injection of allopregnanolone. The sensitivity to allopregnanolone was significantly higher in the patients compared to controls after the first injection (p = 0.04) and the difference increased when the response per allopregnanolone concentration unit was compared ( p = 0.006). Following the flumazenil injection the burnout patients (p= 0.016), but not controls, showed a decrease in SEV and flumazenil acted like a positive modulator that is agonistic. There was no significant difference between the groups after second allopregnanolone injection. In conclusion, patients with work related psychosocial stress and burnout syndrome show a different response to GABA-A receptor modulators than controls suggesting a changed GABA-A receptor function in these patients. More precisely we hypothesize that the alpha 4 and delta subunits are up-regulated elevating the responsiveness to allopregnanolone and change the effect of flumazenil, which provides a potential explanation to the burnout syndrome. Flumazenil does not block the effect of allopregnanolone.

Place, publisher, year, edition, pages
Pergamon Press, 2013
Keyword
Allopregnanolone challenge, Burnout syndrome, Saccadic velocity
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-78957 (URN)10.1016/j.psyneuen.2012.10.014 (DOI)000320412400013 ()
Funder
Swedish Research Council, 4X-11198
Note

This study was funded by grants from Swedish research council, project number 4X-11198, and the EU structural fund, objective 1, Svenska läkaresallskapet, Visare Norr, Umea University Foundations and ALE rnedel from Västerbottens Läns Landsting.

Available from: 2013-07-29 Created: 2013-07-29 Last updated: 2017-12-06Bibliographically approved
Innala, E., Bäckström, T., Sundström Poromaa, I., Andersson, C. & Bixo, M. (2012). Women with acute intermittent porphyria have a defect in 5 alpha-steroid production during the menstrual cycle. Acta Obstetricia et Gynecologica Scandinavica, 91(12), 1445-1452.
Open this publication in new window or tab >>Women with acute intermittent porphyria have a defect in 5 alpha-steroid production during the menstrual cycle
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2012 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 91, no 12, 1445-1452 p.Article in journal (Refereed) Published
Abstract [en]

Objective. To measure serum concentrations of progesterone, estradiol and 5 alpha- and 5 beta-reduced progesterone metabolites in the follicular and luteal phases of the menstrual cycle in women with latent acute intermittent porphyria and manifest acute intermittent porphyria in comparison with healthy control women. Design. A descriptive study with repeated measurements during a complete, ovulatory menstrual cycle. Setting. University hospital out-patient clinic. Population. Thirty-two women with DNA-diagnosed acute intermittent porphyria and 20 healthy control women. Methods. Blood samples for serum progesterone, estradiol, allopregnanolone and pregnanolone were drawn on predefined menstrual cycle days, twice in the follicular phase and three times in the luteal phase. Serum levels of estradiol and progesterone were analysed with commercial kits. Allopregnanolone and pregnanolone levels were analysed with radioimmunoassay following diethylether extraction and celite column chromatography. Main outcome measures. Changes in serum levels of progesterone, estradiol, allopregnanolone and pregnanolone throughout the menstrual cycle. Results. Women with acute intermittent porphyria displayed lower serum concentrations of allopregnanolone in comparison with healthy control women, the difference being most prominent in the luteal phase (p < 0.001). Levels of pregnanolone did not differ significantly between groups. No significant difference was found between women with latent acute intermittent porphyria and manifest acute intermittent porphyria. Conclusions. Decreased levels of the 5 alpha-reduced progesterone metabolite allopregnanolone were found in the menstrual cycle of women with acute intermittent porphyria. This has not been reported previously and could indicate a reduced 5 alpha-reductase type 1 capacity in the ovary and liver among these women.

Place, publisher, year, edition, pages
John Wiley & Sons, 2012
Keyword
Acute intermittent porphyria, menstrual cycle, progesterone, allopregnanolone, pregnanolone
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-63761 (URN)10.1111/j.1600-0412.2012.01536.x (DOI)000312032700015 ()
Available from: 2013-01-14 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved
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