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  • 1.
    Andréen, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Progesterone effects during sequential hormone replacement therapy2003In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 148, no 5, p. 571-577Article in journal (Refereed)
  • 2.
    Andréen, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sharuh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    van Wingen, Guido
    F.C. Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, The Netherlands.
    Fernández, Guillen
    F.C. Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, The Netherlands.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators2009In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 34, no 8, p. 1121-1132Article in journal (Refereed)
    Abstract [en]

    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.

  • 3.
    Andréen, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Spigset, Olav
    Andersson, Agneta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone.2006In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 54, no 3, p. 238-244Article in journal (Refereed)
  • 4.
    Andréen, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andersson, Agneta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone.2005In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, no 2, p. 212-224Article in journal (Refereed)
  • 5.
    Andréen, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone concentration and mood: a bimodal association in postmenopausal women treated with oral progesterone.2006In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 187, no 2, p. 209-221Article in journal (Refereed)
  • 6.
    Bengtsson, Sara K. S.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hedström, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zingmark, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Jonsson, Bjorn
    Bäckström, Torbjörn
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans2015In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 52, p. 22-31Article in journal (Refereed)
    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.

  • 7.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andersson, Agneta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andreén, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Björn, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Haage, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Isaksson, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlott
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundgren, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ödmark, Inga-Stina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zingmark, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Pathogenesis in menstrual cycle-linked CNS disorders.2003In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1007, p. 42-53Article, review/survey (Other academic)
  • 8.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andreen, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Birzniece, Vita
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Björn, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nordenstam-Haghjo, Maud
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    The role of hormones and hormonal treatments in premenstrual syndrome2003In: CNS Drugs, ISSN 1172-7047, E-ISSN 1179-1934, Vol. 17, no 5, p. 325-342Article in journal (Refereed)
    Abstract [en]

    Premenstrual syndrome (PMS) is a menstrual cycle-linked condition with both mental and physical symptoms. Most women of fertile age experience cyclical changes but consider them normal and not requiring treatment. Up to 30% of women feel a need for treatment. The aetiology is still unclear, but sex steroids produced by the corpus luteum of the ovary are thought to be symptom provoking, as the cyclicity disappears in anovulatory cycles when a corpus luteum is not formed. Progestogens and progesterone together with estrogen are able to induce similar symptoms as seen in PMS. Symptom severity is sensitive to the dosage of estrogen. The response systems within the brain known to be involved in PMS symptoms are the serotonin and GABA systems. Progesterone metabolites, especially allopregnanolone, are neuroactive, acting via the GABA system in the brain. Allopregnanolone has similar effects as benzodiazepines, barbiturates and alcohol; all these substances are known to induce adverse mood effects at low dosages in humans and animals. SSRIs and substances inhibiting ovulation, such as gonadotrophin-releasing hormone (GnRH) agonists, have proven to be effective treatments. To avoid adverse effects when high dosages of GnRH agonists are used, add-back hormone replacement therapy is recommended. Spironolactone also has a beneficial effect, although not as much as SSRIs and GnRH agonists.

  • 9.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Maja
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ossewaarde, L
    Ragagnin, Gianna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Savic, I
    Strömberg, J
    Timby, Erika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    van Broekhoven, F
    van Wingen, G
    Allopregnanolone and mood disorders2014In: Progress in Neurobiology, ISSN 0301-0082, E-ISSN 1873-5118, Vol. 113, p. 88-94Article in journal (Refereed)
    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.

  • 10.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Savic, Ivanka
    Increased neurosteroid sensitivity - An explanation to symptoms associated with chronic work related stress in women?2013In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 7, p. 1078-1089Article in journal (Refereed)
    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.

  • 11.
    Hedström, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Spigset, Olav
    Zingmark, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 203, no 1, p. 85-98Article in journal (Refereed)
    Abstract [en]

    Rationale  The pharmacokinetics and behavioral effects of isoallopregnanolone (3β-hydoxy-5α-pregnan-20-one) in women are not known. Objectives  Allopregnanolone (3α-hydoxy-5α-pregnan-20-one) is a well-known neurosteroid, acting via the GABAA receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3β-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABAA receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABAA receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans.

    Materials and methods  Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle.

    Results  Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle.

    Conclusions  After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.

  • 12.
    Hedström, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Sundsvalls sjukhus, Obstetrik och gynekologi.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Does chronic endogenous exposure to neuroactive steroids change receptor sensitivity to allopregnanolone in humans?Manuscript (preprint) (Other academic)
  • 13.
    Hedström, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Gideonsson, Ida
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA A receptor sensitivity to allopregnanolone2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 5, p. 643-650Article in journal (Refereed)
    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.

  • 14.
    Hedström, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in healthy fertile women but not in women with polycystic ovary syndromeManuscript (preprint) (Other academic)
  • 15. Lindahl, Magnus S
    et al.
    Olovsson, Matts
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Thorsen, Kim
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sundström Poromaa, Inger
    Increased cortisol responsivity to adrenocorticotropic hormone and low plasma levels of interleukin-1 receptor antagonist in women with functional hypothalamic amenorrhea.2007In: Fertil Steril, ISSN 1556-5653, Vol. 87, no 1, p. 136-42Article in journal (Refereed)
  • 16. Lundell, I. W.
    et al.
    Frans, O.
    Helstrom, L.
    Hogberg, U.
    Moby, L.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Poromaa, I. S.
    Sydsjo, G.
    Ohman, S. G.
    Ostlund, I
    Svanberg, A. S.
    Post-traumatic stress disorder among women requesting induced termination of pregnancy: a Swedish multi-centre study2012In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 119, no SI, Suppl 2, p. 2-2Article in journal (Other academic)
  • 17. Lundell, Inger Wallin
    et al.
    Poromaa, Inger Sundstrom
    Frans, Orjan
    Helstrom, Lotti
    Hogberg, Ulf
    Moby, Lena
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sydsjo, Gunilla
    Ohman, Susanne Georgsson
    Ostlund, Ingrid
    Svanberg, Agneta Skoog
    The prevalence of posttraumatic stress among women requesting induced abortion2013In: European journal of contraception & reproductive health care, ISSN 1362-5187, E-ISSN 1473-0782, Vol. 18, no 6, p. 480-488Article in journal (Refereed)
    Abstract [en]

    Objectives To describe the prevalence and pattern of traumatic experiences, to assess the prevalence of posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms (PTSS), to identify risk factors for PTSD and PTSS, and to analyse the association of PTSD and PTSS with concomitant anxiety and depressive symptoms in women requesting induced abortion. Methods A Swedish multi-centre study of women requesting an induced abortion. The Screen Questionnaire - Posttraumatic Stress Disorder was used for research diagnoses of PTSD and PTSS. Anxiety and depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS). Results Of the 1514 respondents, almost half reported traumatic experiences. Lifetime-and point prevalence of PTSD were 7% (95% confi dence interval [CI]: 5.8-8.5) and 4% (95% CI: 3.1-5.2), respectively. The prevalence of PTSS was 23% (95% CI: 21.1-25.4). Women who reported symptoms of anxiety or depression when requesting abortion were more likely to have ongoing PTSD or PTSS. Also single-living women and smokers displayed higher rates of ongoing PTSD. Conclusions Although PTSD is rare among women who request an induced abortion, a relatively high proportion suffers from PTSS. Abortion seeking women with trauma experiences and existing or preexisting mental disorders need more consideration and alertness when counselled for termination.

  • 18. Lundell, Inger Wallin
    et al.
    Öhman, Susanne Georgsson
    Frans, Örjan
    Helström, Lotti
    Högberg, Ulf
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström Poromaa, Inger
    Sydsjö, Gunilla
    Östlund, Ingrid
    Svanberg, Agneta Skoog
    Posttraumatic stress among women after induced abortion: a Swedish multi-centre cohort study2013In: BMC Women's Health, ISSN 1472-6874, E-ISSN 1472-6874, Vol. 13, p. Article Number: 52-Article in journal (Refereed)
    Abstract [en]

    Background: Induced abortion is a common medical intervention. Whether psychological sequelae might follow induced abortion has long been a subject of concern among researchers and little is known about the relationship between posttraumatic stress disorder (PTSD) and induced abortion. Thus, the aim of the study was to assess the prevalence of PTSD and posttraumatic stress symptoms (PTSS) before and at three and six months after induced abortion, and to describe the characteristics of the women who developed PTSD or PTSS after the abortion. Methods: This multi-centre cohort study included six departments of Obstetrics and Gynaecology in Sweden. The study included 1457 women who requested an induced abortion, among whom 742 women responded at the three-month follow-up and 641 women at the six-month follow-up. The Screen Questionnaire-Posttraumatic Stress Disorder (SQ-PTSD) was used for research diagnoses of PTSD and PTSS, and anxiety and depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale (HADS). Measurements were made at the first visit and at three and six months after the abortion. The 95% confidence intervals for the prevalence of lifetime or ongoing PTSD and PTSS were calculated using the normal approximation. The chi-square test and the Student's t-test were used to compare data between groups. Results: The prevalence of ongoing PTSD and PTSS before the abortion was 4.3% and 23.5%, respectively, concomitant with high levels of anxiety and depression. At three months the corresponding rates were 2.0% and 4.6%, at six months 1.9% and 6.1%, respectively. Dropouts had higher rates of PTSD and PTSS. Fifty-one women developed PTSD or PTSS during the observation period. They were young, less well educated, needed counselling, and had high levels of anxiety and depressive symptoms. During the observation period 57 women had trauma experiences, among whom 11 developed PTSD or PTSS and reported a traumatic experience in relation to the abortion. Conclusion: Few women developed PTSD or PTSS after the abortion. The majority did so because of trauma experiences unrelated to the induced abortion. Concomitant symptoms of depression and anxiety call for clinical alertness and support.

  • 19.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    How to determine symptom severity in premenstrual syndrome: a combination of daily symptom ratings and interviews.2011In: Sexual and reproductive healthcare, ISSN 1877-5764, Vol. 2, no 4, p. 161-168Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate how premenstrual symptoms are experienced and affect daily life, and to see if there is an agreement in reported symptom severity based on interviews compared to ratings on a symptom rating scale.

    STUDY DESIGN: Twenty-two women with different degree of premenstrual symptoms were interviewed about their symptoms. Based on the luteal-phase interviews, they were categorized in four different severity groups: severe (n=5), moderate (n=3), mild (n=8), and no symptoms/cyclicity (n=6). The interviews were then compared with rated symptom scores, number of expressed symptoms per day, number of days with symptoms, and daily life impairment.

    MAIN OUTCOME MEASURES: Agreement between rated symptom scores and reported symptoms in the interviews.

    RESULTS: Comparing seven days in luteal phase scorings with interview data the group with no symptoms/cyclicity showed high agreement between severities reported in the interviews and daily rated scores. Among women who reported severe symptoms, an agreement was seen in three out of five. In the mild/moderate group, the agreement was less conclusive. The day of interview there was a high agreement between data from the reported symptom ratings and symptoms reported in the interview.

    CONCLUSION: Rated symptom scores the day of interview reflects well symptoms reported in the interviews. Mean symptom scores for seven luteal phase days showed an agreement between symptom ratings and symptoms expressed in interviews among women with severe symptoms and no symptoms/cyclicity. In the group with mild/moderate symptoms, data was less conclusive.

  • 20.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Mood and physical symptoms improve in women with severe cyclical changes by taking an oral contraceptive containing 250-mcg norgestimate and 35-mcg ethinyl estradiol2013In: Contraception, ISSN 0010-7824, E-ISSN 1879-0518, Vol. 87, no 6, p. 773-781Article in journal (Refereed)
    Abstract [en]

    Background: The purpose of this study was to investigate how women without and with different severity of premenstrual symptoms react to treatment with a combined oral contraceptive containing 250-mcg norgestimate/35-mcg ethinyl estradiol (EE). Focus was placed on mood and physical symptoms. Study Design: This open, prospective study evaluated 24 women using norgestimate/EE for three cycles in a 21/7 regimen. Symptoms and bleeding pattern were captured by daily ratings on the Cyclicity Diagnoser scale. Results: Women with severe premenstrual mood symptoms improved in summarized negative mood (p<.001) and summarized positive mood (p<.05), as well as in swelling (p<.05) and effect on daily life (p<.05). Women with no or mild or moderate symptoms did not show any significant improvement or deterioration in any symptom after 3 months of treatment. Conclusions: Norgestimate 250 mcg/EE 35 mcg significantly improved premenstrual summarized negative mood symptoms during 3 treatment months compared to pretreatment in women with severe premenstrual symptoms, together with improvement in positive symptoms, swelling and effect on daily life. (C) 2013 Elsevier Inc. All rights reserved.

  • 21.
    Nyberg, Sigrid
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andersson, Agneta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zingmark, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    The effect of a low dose of alcohol on allopregnanolone serum concentrations across the menstrual cycle in women with severe premenstrual syndrome and controls.2005In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, no 9, p. 892-901Article in journal (Refereed)
  • 22.
    Nyberg, Sigrid
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zingmark, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Purdy, Robert H
    Poromaa, Inger Sundström
    Allopregnanolone decrease with symptom improvement during placebo and gonadotropin-releasing hormone agonist treatment in women with severe premenstrual syndrome2007In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 23, no 5, p. 257-266Article in journal (Refereed)
  • 23.
    Nyberg, Sigrid
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Poromaa, Inger Sundström
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    No difference in responsiveness to a low dose of alcohol between healthy women and men.2004In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 78, no 3, p. 603-610Article in journal (Refereed)
  • 24.
    Nyberg, Sigrid
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Altered sensitivity to alcohol in the late luteal phase among patients with premenstrual dysphoric disorder.2004In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 29, no 6, p. 767-777Article in journal (Refereed)
  • 25.
    Segebladh, Birgitta
    et al.
    Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.
    Bannbers, Elin
    Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.
    Kask, Kristiina
    Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Heimer, Gun
    Uppsala Univ, Natl Ctr Knowledge Mens Violence Women, Uppsala, Sweden. Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.
    Sundström-Poromaa, Inger
    Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.
    Prevalence of violence exposure in women with premenstrual dysphoric disorder in comparison with other gynecological patients and asymptomatic controls2011In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 90, no 7, p. 746-52Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of the present study was to estimate prevalence rates of physical, emotional and sexual abuse in women with premenstrual dysphoric disorder (PMDD) in comparison with gynecological outpatients and asymptomatic healthy control subjects.

    DESIGN: Cross-sectional study.

    SETTINGS: Departments of obstetrics and gynecology in three different Swedish hospitals.

    POPULATION: Fifty-eight women meeting strict criteria for PMDD, a control group of 102 women seeking care at the gynecological outpatient clinic (ObGyn controls) and 47 asymptomatic healthy control subjects were included in this study.

    METHODS: The Swedish version of the Abuse Assessment Screen was used to collect information on physical and sexual abuse, and the screening instrument was administered as a face-to-face interview.

    MAIN OUTCOME MEASURES: Previous and ongoing physical and sexual abuse.

    RESULTS: Any lifetime abuse (physical, emotional or sexual) was reported by 31.0% of PMDD patients, by 39.2% of ObGyn controls and by 21.3% of healthy controls. The ObGyn controls reported physical and/or emotional abuse significantly more often than PMDD patients as well as healthy controls (p<0.05). Lifetime sexual abuse was reported significantly more often by ObGyn controls than by healthy controls (p<0.05).

    CONCLUSIONS: Patients with PMDD appear not to have suffered physical, emotional or sexual abuse to a greater extent than other gynecological patients or healthy control subjects. However, exposure to violence was common in all groups of interviewed women, and for the individual patient these experiences may contribute to their experience of symptoms.

  • 26.
    Segebladh, Birgitta
    et al.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Borgström, Anna
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing hormone agonist treatment in patients with premenstrual dysphoric disorder2009In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 201, no 2, p. 139.e1-139.e8Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to investigate which add-back hormone replacement therapy would be most beneficial in terms of mood effects for patients with premenstrual dysphoric disorder who are receiving gonadotropin-releasing hormone agonist therapy.

    STUDY DESIGN: Three different add-back hormone replacement treatments were evaluated in a randomized, double-blinded, cross-over clinical trial in 27 patients premenstrual dysphoric disorder. The add-back treatments consisted of 1.5 mg estradiol and 400 mg progesterone, 1.5 mg estradiol and placebo, and 0.5 mg estradiol and 400 mg progesterone. The primary outcome measure was daily symptom ratings for mood and physical symptoms.

    RESULTS: The highest dose of estradiol in combination with progesterone was associated with the most pronounced symptom recurrence, both in comparison with a lower dose of estradiol together with progesterone and estradiol-only treatment.

    CONCLUSION: Based on the findings of the present study, long-cycle add-back treatment to avoid frequent progestagen use appears to be most beneficial for patients with premenstrual dysphoric disorder.

  • 27.
    Sundström, I
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, M
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hammarbäck, S
    Bäckström, T
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Treatment of premenstrual syndrome with gonadotropin-releasing hormone agonist in a low dose regimen1999In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 78, no 10, p. 891-899Article in journal (Refereed)
  • 28. Söderberg, Karin
    et al.
    Sundström Poromaa, Inger
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nordh, Erik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Psychophysically determined thresholds for thermal perception and pain perception in healthy women across the menstrual cycle.2006In: Clin J Pain, ISSN 0749-8047, Vol. 22, no 7, p. 610-6Article in journal (Refereed)
  • 29. Tiihonen Möller, Anna
    et al.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sondergaard, Hans Peter
    Helström, Lotti
    Women with PTSD have a changed sensitivity to GABA-A receptor active substances2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 11, p. 2025-2033Article in journal (Refereed)
    Abstract [en]

    The use of benzodiazepines in treating anxiety symptoms in patients with posttraumatic stress disorder (PTSD) has been debated. Studies on other anxiety disorders have indicated changed sensitivity to GABA-A receptor active substances. In the present study, we investigated the GABA receptor sensitivity in PTSD patients. Injections of allopreganolone, diazepam, and flumazenil were carried out, each on separate occasions, in 10 drug na < ve patients with PTSD compared to 10 healthy controls. Effects were measured in saccadic eye velocity (SEV) and in subjective ratings of sedation. The PTSD patients were less sensitive to allopregnanolone compared with healthy controls. This was seen as a significant difference in SEV between the groups (p = 0.047). Further, the patients were less sensitive to diazepam, with a significant less increase in sedation compared to controls (p = 0.027). After flumazenil injection, both patients and controls had a significant agonistic effect on SEV, leading to decreased SEV after injection. The patients also responded with an increase in sedation after flumazenil injection, while this was not seen in the controls. Patients with PTSD have a changed sensitivity to GABA-A receptor active substances. As a consequence of this, benzodiazepines and other GABA-A receptor active compounds such as sleeping pills will be less useful for this group of patients.

  • 30.
    Timby, Erika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Balgård, Matts
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Spigset, Olav
    Andersson, Agneta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Porankiewicz-Asplund, Joanna
    Purdy, Robert H
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Poromaa, Inger Sundström
    Pharmacokinetic and behavioral effects of allopregnanolone in healthy women2006In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 186, no 3, p. 414-424Article in journal (Refereed)
    Abstract [en]

    Rationale  The behavioral effects of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) in women are not known. Objective  Allopregnanolone, a neuroactive steroid secreted by the mammalian ovary, exerts its anesthetic, anxiolytic, and sedative/hypnotic effects through potentiation of GABAA receptors. The purpose of this study was to evaluate the behavioral effects of allopregnanolone in healthy women. Methods  Ten healthy women were given three increasing intravenous doses of allopregnanolone in the follicular phase of the menstrual cycle. Saccadic eye movement parameters and visual analogue scales of sedation were used to evaluate the behavioral response of allopregnanolone. Repeated blood samples for analyses of allopregnanolone were drawn throughout the study day. Results  Exogenously administered allopregnanolone decreases saccadic eye movement parameters and increases subjective ratings of sedation that correlate with increased serum concentrations of this neuroactive steroid. Conclusion  The behavioral effects of allopregnanolone are similar to that of its 5β-stereoisomer, pregnanolone (3α-hydroxy-5β-pregnan-20-one). Apart from fatigue and mild nausea, allopregnanolone given in a cumulative dose of 0.09 mg/kg did not have any adverse effects.

  • 31.
    Timby, Erika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wihlbäck, Anna-Carin N
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone sensitivity over the menstrual cycle and during oral contraceptivesManuscript (preprint) (Other academic)
  • 32.
    Timby, Erika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wihlbäck, Anna-Carin N
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls — a pilot study2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 11, p. 2109-2117Article in journal (Refereed)
    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.

  • 33.
    Timby, Erika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hedström, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone, a GABA-A receptor agonist, decreases gonadotropin levels in women: a preliminary study2011In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 27, no 12, p. 1087-1093Article in journal (Refereed)
    Abstract [en]

    Animal studies suggest regulatory effects on the hypothalamic-pituitary-gonad axis by allopregnanolone, an endogenous gamma-aminobutyric acid A (GABAA) receptor agonist. Elevated levels of allopregnanolone in women with hypothalamic amenorrhea have been seen. Isoallopregnanolone is an isomer to allopregnanolone, but without GABAA receptor effects. The purpose of this study was to investigate effects of allopregnanolone and isoallopregnanolone on gonadotropin levels in healthy women of fertile age. Ten women were given allopregnanolone and five women isoallopregnanolone intravenously in follicular phase. Repeated blood samples were drawn during the test day. Main outcomes were changes in serum levels of follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, and progesterone. Serum-FSH decreased between 5 and 105 min after the allopregnanolone injection (F(16,144)=2.18, p=0.008). Serum-LH was reduced between 5 and 35 min following the allopregnanolone injection (F(16,144)=2.63, p=0.001). Serum-oestradiol and -progesterone were not significantly changed after allopregnanolone injections. No effect on gonadotropin levels were seen after administration of isoallopregnanolone. Allopregnanolone reduces FSH and LH levels in women and the effect might be mediated via a specific GABAA receptor activation since isoallopregnanolone lacked this effect. Although the number of women was small, the results suggest a regulatory mechanism on the hypothalamic-pituitary-gonadal axis by allopregnanolon.

  • 34.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hedström, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Gideonsson, Ida
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    The author's reply: Blood allopregnanolone levels in women with polycystic ovary syndrome2016In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 85, no 1, p. 152-154Article in journal (Refereed)
  • 35.
    Wihlbäck, Anna-Carin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andersson, Agneta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone serum concentrations and neurosteroid sensitivity during withdrawal from postmenopausal hormone therapy.2007In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Gynecol Endocrinol, Vol. 23, no 10, p. 590-596Article in journal (Refereed)
  • 36.
    Wihlbäck, Anna-Carin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Estradiol and the addition of progesterone increase the sensitivity to a neurosteroid in postmenopausal women2005In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, no 1, p. 38-50Article in journal (Refereed)
  • 37.
    Wihlbäck, Anna-Carin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, S
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, T
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sensitivity to a neurosteroid is increased during the progestagen addition of postmenopausal hormone replacement therapy2001In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 73, p. 397-407Article in journal (Refereed)
1 - 37 of 37
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