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  • 1. Alexandersson, Olof
    et al.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Högberg, Ulf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Evidence-based changes in term breech delivery practice in Sweden.2005In: Acta Obstet Gynecol Scand, ISSN 0001-6349, Vol. 84, no 6, p. 584-7Article in journal (Refereed)
  • 2.
    Andersson, Liselott
    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.
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bondestam, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Åström, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Point prevalence of psychiatric disorders during the second trimester of pregnancy: a population-based study.2003In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 189, no 1, p. 148-154Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: This study was undertaken to determine the point prevalence of psychiatric disorders during the second trimester of pregnancy in a population-based sample of pregnant women. STUDY DESIGN: Participants were 1795 consecutive pregnant women attending routine ultrasound screening at two obstetric clinics in Northern Sweden during 1 year. The Primary Care Evaluation of Mental Disorders (PRIME-MD) was used for evaluating. RESULTS: Overall, 1734 (96.6%) of the women filled in the PRIME-MD patient questionnaire. Psychiatric disorders were present in 14.1% of the women. Major depression was prevalent in 3.3% of patients and minor depression in 6.9% of patients. Anxiety disorders were encountered in 6.6% of patients. Women with psychiatric disorders displayed significantly more somatic symptoms and more pronounced fear of childbirth. Among diagnosed patients, only 5.5% had some form of treatment. CONCLUSION: The prevalence of mood and anxiety disorders in this unselected population of pregnant women was high and the majority of the women were found to be undiagnosed and untreated.

  • 3.
    Andersson, Liselott
    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.
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Åström, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Depression and anxiety during pregnancy and six months postpartum: a follow-up study2006In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 85, no 8, p. 937-944Article in journal (Refereed)
    Abstract [en]

    AIMS: To investigate the relationship between antenatal and postpartum depression and anxiety and to explore associated maternal characteristics. METHODS: From a population-based sample of 1,555 women attending two obstetric clinics in Sweden, all women with an antenatal psychiatric diagnosis (n = 220) and a random selection of healthy women (n = 500) were contacted for a second assessment three to six months postpartum. The Primary Care Evaluation of Mental Disorders was used for evaluation on both occasions. RESULTS: Fewer cases of depressive and/or anxiety disorders were prevalent postpartum compared with the second trimester screening. Depression and/or anxiety were prevalent in 16.5% of postpartal women versus 29.2% of pregnant women. There was a significant shift from a majority of subthreshold diagnoses during pregnancy to full Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnoses during the postpartum period. A history of previous psychiatric disorder, living single, and obesity were significantly associated with a new-onset postpartum psychiatric disorder. The absence of a previous psychiatric disorder was significantly associated with a postpartum recovery of depression or anxiety. CONCLUSIONS: Depression and anxiety appear to be less common postpartum than during pregnancy.

  • 4.
    Andersson, Liselott
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Department of Obstetrics and Gynecology, Sunderby Hospital, Luleå, Sweden.
    Sundström-Poromaa, Inger
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Åström, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Implications of antenatal depression and anxiety for obstetric outcome2004In: Obstetrics and Gynecology, ISSN 0029-7844, E-ISSN 1873-233X, Vol. 104, no 3, p. 467-476Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the obstetric outcome and health care consumption during pregnancy, delivery, and the early postpartum period in an unselected population-based sample of pregnant women diagnosed with antenatal depressive and/or anxiety disorders, compared with healthy subjects. METHODS: Participants were 1,495 women attending 2 obstetric clinics in Northern Sweden. The Primary Care Evaluation of Mental Disorders was used to evaluate depressive and anxiety disorders in the second trimester of pregnancy. To assess demographic characteristics, obstetric outcome, and complications, the medical records of the included women were reviewed. RESULTS: Significant associations were found between depression and/or anxiety and increased nausea and vomiting, prolonged sick leave during pregnancy and increased number of visits to the obstetrician, specifically, visits related to fear of childbirth and those related to contractions. Planned cesarean delivery and epidural analgesia during labor were also significantly more common in women with antenatal depression and/or anxiety. CONCLUSION: There is an association between antenatal depressive and/or anxiety disorders and increased health care use (including cesarean deliveries) during pregnancy and delivery.

  • 5.
    Andersson, Liselott
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Åström, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Neonatal outcome following maternal antenatal depression and anxiety: a population-based study.2004In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 159, no 9, p. 872-881Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine neonatal outcomes among women who had depressive and anxiety disorders during the second trimester of pregnancy in a population-based sample. Participants were 1,465 women and their neonates born at two obstetric clinics in Sweden. The inclusion period for the women was October 2, 2000-October 1, 2001. The Primary Care Evaluation of Mental Disorders (PRIME-MD) classification system was used to evaluate mental disorders in the second trimester of pregnancy. For assessment of demographic characteristics, birth statistics, and birth-related complications, the medical records of the included women and their offspring were reviewed after delivery. The study results revealed no differences in neonatal outcome between women with antenatal depressive disorders and/or anxiety disorders and healthy subjects. The authors conclude that neonatal outcome did not deteriorate despite the women's impaired mental health during pregnancy.

  • 6.
    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)
  • 7.
    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)
  • 8.
    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)
  • 9.
    Bendix, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ahokas, Antti
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Allopregnanolone and progesterone in estradiol treated severe postpartum affective disorder2019In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 107, p. 68-68Article in journal (Other academic)
  • 10.
    Bendix, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience / Centre for Psychiatry Research & Stockholm Health Care Services, Stockholm County Council, Karolinska Institutet, Stockholm, Sweden.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ahokas, Antti
    Mehiläinen Clinic, Helsinki, Finland .
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience / Centre for Psychiatry Research & Stockholm Health Care Services, Stockholm County Council, Karolinska Institutet, Stockholm, Sweden.
    Allopregnanolone and progesterone in estradiol treated severe postpartum depression and psychosis: Preliminary findings2019In: Neurology, psychiatry and brain research, ISSN 0941-9500, Vol. 34, p. 50-57Article in journal (Refereed)
    Abstract [en]

    Background: Postpartum affective disorders may be associated with dysregulation of gonadal steroids. We investigated peripheral levels of allopregnanolone and progesterone in a combined group of women with postpartum onset of severe depression and/or psychosis who, as previously reported, responded with rapid symptom remission during sublingual estradiol treatment. The aim was to assess differences in allopregnanolone and progesterone between patients and healthy controls at baseline, and hormonal changes during estradiol treatment and symptom remission in patients.

    Methods: Allopregnanolone and progesterone in serum were analyzed with radioimmunoassay before and four weeks after initiation of sublingual estradiol treatment in ten women with postpartum depression and four women with postpartum psychosis (ICD-10). Twenty-eight healthy postpartum controls were included for baseline comparison.

    Results: Allopregnanolone declined significantly during estradiol treatment while there was a trend for lower baseline allopregnanolone levels in patients compared with healthy postpartum controls. The ratio between allopregnanolone and progesterone was significantly lower in patients compared with controls and it remained unchanged after clinical recovery.

    Limitations: This study is a secondary analysis of two estradiol treatment studies based on availability of samples for the analysis of allopregnanolone. Healthy controls were assessed earlier after delivery. Data on potential confounders (somatic health, breastfeeding, other medication) were not available.

    Conclusions: These preliminary findings suggest that clinical recovery of severe postpartum depression and psychosis during estradiol treatment does not seem to depend on increasing levels of allopregnanolone. Differences in progesterone metabolism may constitute a risk factor for severe postnatal affective dysregulation.

  • 11. Bengtsdotter, Hanna
    et al.
    Lundin, Cecilia
    Gemzell Danielsson, Kristina
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Baumgart, Juliane
    Marions, Lena
    Brynhildsen, Jan
    Malmborg, Agota
    Lindh, Ingela
    Sundström Poromaa, Inger
    Ongoing or previous mental disorders predispose to adverse mood reporting during combined oral contraceptive use2018In: European journal of contraception & reproductive health care, ISSN 1362-5187, E-ISSN 1473-0782, Vol. 23, no 1, p. 45-51Article in journal (Refereed)
    Abstract [en]

    Purpose: Previous studies have emphasised that women with pre-existing mood disorders are more inclined to discontinue hormonal contraceptive use. However, few studies have examined the effects of combined oral contraceptives (COC) on mood in women with previous or ongoing mental disorders.

    Materials and methods: This is a supplementary analysis of an investigator-initiated, double-blinded, randomised clinical trial during which 202 women were treated with either a COC (1.5mg estradiol and 2.5mg nomegestrolacetate) or placebo during three treatment cycles. The Mini International Neuropsychiatric Interview was used to collect information on previous or ongoing mental disorders. The primary outcome measure was the total change score in five mood symptoms on the Daily Record of Severity of Problems (DRSP) scale in the intermenstrual phase of the treatment cycle.

    Results: Women with ongoing or previous mood, anxiety or eating disorders allocated to COC had higher total DRSP Δ-scores during the intermenstrual phase of the treatment cycle in comparison with corresponding women randomised to placebo, mean difference 1.3 (95% CI 0.3-2.3). In contrast, among women without mental health problems, no difference in total DRSP Δ-scores between COC- and placebo users was noted. Women with a risk use of alcohol who were randomised to the COC had higher total DRSP Δ-scores than women randomised to placebo, mean difference 2.1 (CI 95% 1.0-3.2).

    Conclusions: Women with ongoing or previous mental disorders or risk use of alcohol have greater risk of COC-induced mood symptoms. This may be worth noting during family planning and contraceptive counselling.

  • 12.
    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.

  • 13.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Centrum för obstetrik och gynekologi Västerbotten, Norrlands universitetssjukhus, Umeå, Sverige.
    Gynekologisk anamnes och undersökningsmetoder2022In: Problemorienterad gynekologi och obstetrik / [ed] Marie Bixo; Inger Sundström Poromaa, Stockholm: Liber, 2022, 2, p. 28-43Chapter in book (Other academic)
  • 14.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Centrum för obstetrik och gynekologi Västerbotten, Norrlands universitetssjukhus, Umeå, Sverige.
    Klimakteriebesvär2022In: Problemorienterad gynekologi och obstetrik / [ed] Marie Bixo; Inger Sundström Poromaa, Stockholm: Liber, 2022, 2, p. 225-234Chapter in book (Other academic)
  • 15.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Norrlands universitetssjukhus, Umeå, Sverige.
    Klimakteriet2022In: Gynekologi / [ed] Torbjörn Bäckström; Preben Kjølhede; Britt-Marie Landgren, Lund: Studentlitteratur AB, 2022, 3, p. 97-107Chapter in book (Other academic)
  • 16.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ovarian steroids in rat and human brain: effects of different endocrine states1987Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ovarian steroid hormones are known to produce several different effects in the brain. In addition to their role in gonadotropin release, ovulation and sexual behaviour they also seem to affect mood and emotions, as shown in women with the premenstrual tension syndrome. Some steroids have the ability to affect brain excitability. Estradiol decreases the electroshock threshold while progesterone acts as an anti-convulsant and anaesthetic in both animals and humans. Several earlier studies have shown a specific uptake of several steroids in the animal brain but only a few recent studies have established the presence of steroids in the human brain.

    In the present studies, the dissections of rat and human brains were carried out macroscopically and areas that are considered to be related to steroid effects were chosen. Steroid concentrations were measured by radioimmunoassay after extraction and separation with celite chromatography. The accuracy and specificity of these methods were estimated.

    In the animal studies, immature female rats were treated with Pregnant Mare's Serum Gonadotropin (PMSG) to induce simultaneous ovulations. Concentrations of estradiol and progesterone were measured in seven brain areas pre- and postovulatory. The highest concentration of estradiol, pre- and postovulatory, was found in the hypothalamus and differences between the two cycle phases were detected in most brain areas. The preovulatory concentrations of progesterone were low and the highest postovulatory concentration was found in the cerebral cortex.

    In one study, the rats were injected with pharmacological doses of progesterone to induce "anaesthesia". High uptake of progesterone was found and a regional variation in the formation of 5<*-pregnane-3,20-dione in the brain with the highest ratio in the medulla oblongata.

    Concentrations of progesterone, 5a-pregnane-3*20-dione, estradiol and testosterone were determined in 17 brain areas of fertile compared to postmenopausal women. All steroids displayed regional differences in brain concentrations. Higher concentrations of estradiol and progesterone were found in the fertile compared to the postmenopausal women.

    In summary, these studies show that the concentrations of ovarian steroids in the brain are different at different endocrine states in both rats and humans and that there are regional differences in brain steroid distribution.

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  • 17.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Reply2006In: Menopause: The Journal of the North American Menopause, ISSN 1072-3714, E-ISSN 1530-0374, Vol. 13, no 3, p. 538-538Article in journal (Other academic)
  • 18.
    Bixo, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Norrlands universitetssjukhus.
    Brynhildsen, Jan
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ellis, Joy
    Gemzell Danielsson, Kristina
    Kopp Kallner, Helena
    Storck Lindholm, Elisabeth
    Marions, Lena
    Milsom, Ian
    von Schoultz, Bo
    Skalkidou, Alkistis
    Sundström Poromaa, Inger
    Sääv, Inger
    Thunell, Louise
    Tydén, Tanja
    Praktisk preventivmedelsguide2020 (ed. 3)Book (Other academic)
  • 19.
    Bixo, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ekberg, Karin
    Poromaa, Inger Sundstrom
    Hirschberg, Angelica Linden
    Jonasson, Aino Fianu
    Andreen, Lotta
    Timby, Erika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Wulff, Marianne
    Ehrenborg, Agneta
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Treatment of premenstrual dysphoric disorder with the GABA(A) receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial2017In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 80, p. 46-55Article in journal (Refereed)
    Abstract [en]

    Context: Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models.

    Objective: The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD). The pharmacokinetic parameters of UC1010 when given as a subcutaneous injection were measured in healthy women prior to the study in women with PMDD.

    Design: This was an explorative randomized, double-blind, placebo-controlled study.

    Setting: Swedish multicentre study with 10 centers.

    Participants: Participants were 26 healthy women in a pharmacokinetic phase I study part, and 126 women with PMDD in a phase II study part. Diagnosis followed the criteria for PMDD in DSM-5 using Daily Record of Severity of Problems (DRSP) and Endicott’s algorithm.

    Intervention: Subjects were randomized to treatment with UC1010 (10 or 16 mg) subcutaneously every second day during the luteal phase or placebo during one menstrual cycle.

    Outcome measures: The primary outcome measure was the sum of all 21 items in DRSP (Total DRSP score). Secondary outcomes were Negative mood score i.e. the ratings of the 4 key symptoms in PMDD (anger/irritability, depression, anxiety and lability) and impairment (impact on daily life).

    Results: 26 healthy women completed the pharmacokinetic phase I study and the dosing in the following trial was adjusted according to the results. 106 of the 126 women completed the phase II study. Within this group, a significant treatment effect with UC1010 compared to placebo was obtained for the Total DRSP score (p = 0.041) and borderline significance (p = 0.051) for the sum of Negative mood score.

    Nineteen participants however showed symptoms during the follicular phase that might be signs of an underlying other conditions, and 27 participants had not received the medication as intended during the symptomatic phase. Hence, to secure that the significant result described above was not due to chance, a post hoc sub-group analysis was performed, including only women with pure PMDD who completed the trial as intended (n = 60). In this group UC1010 reduced Total DRSP scores by 75% compared with 47% following placebo; the effect size 0.7 (p = 0.006), and for sum of Negative mood score (p = 0.003) and impairment (p = 0.010) with the effect size 0.6. No severe adverse events were reported during the treatment and safety parameters (vital signs and blood chemistry) remained normal during the study.

    Conclusions: This explorative study indicates promising results for UC1010 as a potential treatment for PMDD. The effect size was comparable to that of SSRIs and drospirenone containing oral contraceptives. UC1010 was well tolerated and deemed safe.

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  • 20.
    Bixo, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Johansson, Maja
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Timby, Erika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Michalski, Louise
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder2018In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 30, no 2, article id e12553Article in journal (Refereed)
    Abstract [en]

    Premenstrual dysphoric disorder (PMDD) afflicts 3%-5% of women of childbearing age, and is characterised by recurrent negative mood symptoms (eg, irritability, depression, anxiety and emotional lability) during the luteal phase of the menstrual cycle. The aetiology of PMDD is unknown, although a temporal association with circulating ovarian steroids, in particular progesterone and its metabolite allopregnanolone, has been established during the luteal phase. Allopregnanolone is a positive modulator of the GABA(A) receptor: it is sedative in high concentrations but may precipitate paradoxical adverse effects on mood at levels corresponding to luteal phase concentrations in susceptible women. Saccadic eye velocity (SEV) is a measure of GABA(A) receptor sensitivity; in experimental studies of healthy women, i.v. allopregnanolone decreases SEV. Women with PMDD display an altered sensitivity to an i.v. injection of allopregnanolone compared to healthy controls in this model. In functional magnetic resonance imaging (fMRI) studies, women with PMDD react differently to emotional stimuli in contrast to controls. A consistent finding in PMDD patients is increased amygdala reactivity during the luteal phase. Post-mortem studies in humans have revealed that allopregnanolone concentrations vary across different brain regions, although mean levels in the brain also reflect variations in peripheral serum concentrations. The amygdala processes emotions such as anxiety and aggression. This is interesting because allopregnanolone is detected at high concentrations within the region into which marked increases in blood flow are measured with fMRI following progesterone/allopregnanolone administration. Allopregnanolone effects are antagonised by its isomer isoallopregnanolone (UC1010), which significantly reduces negative mood symptoms in women with PMDD when administered s.c. in the premenstrual phase. This was shown in a randomised, placebo-controlled clinical trial in which the primary outcome was change in symptom scoring on the Daily Rating of Severity of Problems (DRSP): the treatment reduced negative mood scores (P<.005), as well as total DRSP scores (P<.01), compared to placebo in women with PMDD. In conclusion, the underlying studies of this review provide evidence that allopregnanolone is the provoking factor behind the negative mood symptoms in PMDD and that isoallopregnanolone could ameliorate the symptoms as a result of its ability to antagonise the allopregnanolone effect on the GABA(A) receptor.

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  • 21.
    Bixo, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindén Hirschberg, Angelica
    Ännu inte visat att östradiol och »naturligt« progesteron är säkert2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, no 11, article id DAXWArticle in journal (Refereed)
  • 22.
    Bixo, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Lindén Hirschberg, Angelica
    Karolinska institutet, Stockholm, Sverige.
    Ännu inte visat att östradiol och »naturligt« progesteron är säkert: Evidens saknas för bröst- och endometrieskydd2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, no 11, article id DAXWArticle in journal (Other (popular science, discussion, etc.))
  • 23.
    Björn, Inger
    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.
    Strandberg Nöjd, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Collberg, P.
    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.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    The impact of different doses of medroxyprogesterone acetate on mood symptoms in sequential hormonal therapy2002In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 16, p. 1-8Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to compare adverse mood effects of two different doses of medroxyprogesterone acetate (MPA) during postmenopausal hormone replacement therapy (HRT) in women with and without a history of premenstrual syndrome (PMS). The study was designed as a randomized double-blind cross-over study and included 36 postmenopausal women at three health care areas in northern Sweden. The women received 2 mg estradiol continuously during five 28-day cycles and 10 mg or 20 mg MPA sequentially for 12 days during each cycle. The main outcome measures were mood and physical symptoms noted on a daily rating scale. We found that physical symptoms did not differ between 10 and 20 mg MPA. Both women with a history of PMS and women without responded with more negative mood symptoms with the lower dose of MPA. In women with previous PMS the higher dose of MPA enhanced positive mood symptoms. With respect to mood and physical symptoms, the aim to lower MPA doses in HRT is unwarranted.

  • 24.
    Björn, Inger
    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.
    Strandberg Nöjd, Karin
    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.
    Negative mood changes during hormone replacement therapy: a comparison between two progestogens2000In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 183, no 6, p. 1419-1426Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to compare side effects of medroxyprogesterone acetate and norethindrone acetate during postmenopausal hormone replacement therapy in women with and without a history of premenstrual syndrome. Study Design: Fifty-one postmenopausal women were randomly selected in a double-blind crossover study. The women received 2 mg of estradiol continuously during five 28-day cycles and 10 mg of medroxyprogesterone or 1 mg of norethindrone sequentially for 12 days of each cycle. Daily symptom rating scales were kept. Results: The women showed cyclic changes, with negative mood and physical symptoms culminating during the late progestogen phase and positive mood during the estrogen-only phase. Symptoms declined with time but remained after 5 months. Women with a history of premenstrual syndrome responded strongly to both progestogens. Medroxyprogesterone acetate induced less negative and more positive mood symptoms than norethindrone in women with no history of premenstrual syndrome. In both groups medroxyprogesterone caused more physical symptoms than norethindrone. Conclusion: The addition of medroxyprogesterone to estrogen is preferable to norethindrone with respect to mood symptoms in women without a history of premenstrual syndrome.

  • 25.
    Björn, Inger
    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, Gunnel
    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.
    Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy2003In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, no 5, p. 2026-2030Article in journal (Refereed)
    Abstract [en]

    Previous studies have indicated that the addition of progestinsduring sequential hormonal replacement therapy (HRT)causes negative mood and physical symptoms. History of premenstrualsyndrome, type of progestin, and dose of progestinhave thus far been shown to influence the progestin-inducedadverse mood symptoms during HRT.

    The aim of this study was to compare adverse mood effectsof two different doses of estradiol, in combination with a progestin,during postmenopausal HRT. Twenty-eight perimenopausalwomen were included in this randomized, doubleblind,crossover study comparing 2- or 3-mg continuousestradiol, with an addition of 10 mg medroxyprogesteroneacetate on d 17–28 during each treatment cycle. The mainoutcome measures were mood and physical symptoms kept ona daily rating scale. Together with the progestin, the higherdose of estrogen caused significantly more negative moodsymptoms than the lower dose. Tension, irritability, and depressedmood were all significantly augmented during theprogestin phase of cycles with 3mg estradiol (P<0.001). Physicalsymptoms also increased during the progestin phase of3-mg estradiol cycles (P<0.001), whereas positive mood symptomswere less affected. The only positive mood that changedwith estrogen dose was friendliness, which decreased duringthe progestin phase of high estradiol cycles compared withcycles with lower estradiol (P < 0.05).

    Our conclusion is that an increase of the estrogen doseaccentuates negativemoodand physical symptoms during theprogestin phase of sequential hormonal therapy.

  • 26.
    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)
  • 27.
    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.

  • 28.
    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.

  • 29.
    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.
    Strömberg, Jessica
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    GABAA Receptor-Modulating Steroids in Relation to Women’s Behavioral Health2015In: Current Psychiatry Reports, ISSN 1523-3812, E-ISSN 1535-1645, Vol. 17, no 11, article id 92Article, review/survey (Refereed)
    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.

  • 30.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Das, Roshni
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Positive GABAA receptor modulating steroids and their antagonists: Implications for clinical treatments2022In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 34, no 2, article id e13013Article, review/survey (Refereed)
    Abstract [en]

    GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABAA receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti-depressant. However, it is well established that, in certain individuals, GABAA receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3β-OH sibling of Allo, functions as a GABAA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABAA receptors. The antagonistic effect is noted in most GABAA subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo-induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABAA system.

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  • 31.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ekberg, Karin
    Asarina Pharma AB Clinical Research & Development c/o COBIS, Ole Maaloes Vej 3, Kobenhavn N, Denmark.
    Lindén Hirschberg, Angelica
    Karolinska University Hospital, Stockholm, Sweden.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Epperson, C. Neill
    Department of Psychiatry, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, Guinea-Bissau.
    Briggs, Paula
    Liverpool Women's NHS, Liverpool, United Kingdom.
    Panay, Nick
    Imperial College London, UK, London, United Kingdom.
    O'Brien, Shaughn
    Royal Stoke University Hospital, Stoke-on-Trent, United Kingdom.
    A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder2021In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 133, article id 105426Article in journal (Refereed)
    Abstract [en]

    Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified.

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  • 32.
    Comasco, Erika
    et al.
    Department of Neuroscience, Science for Life Laboratory, Sweden.
    Kallner, Helena Kopp
    Department of Clinical Sciences at Danderyd Hospital Karolinska Institutet, Department of Obstetrics and Gynecology, Danderyd Hospital, Stockholm, Sweden.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Hirschberg, Angelica L.
    Department of Women's and Children's Health, Karolinska Institutet, Department of Gynecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Nyback, Sara
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    De Grauw, Haro
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Epperson, C. Neill
    Department of Psychiatry, University of Colorado School of Medicine, Aurora, United States.
    Sundström-Poromaa, Inger
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Ulipristal acetate for treatment of premenstrual dysphoric disorder: A proof-of-concept randomized controlled trial2021In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 178, no 3, p. 256-265Article in journal (Refereed)
    Abstract [en]

    Objective: Premenstrual dysphoric disorder (PMDD) is a common mood disorder, characterized by distressing affective, behavioral, and somatic symptoms in the late luteal phase of the menstrual cycle. The authors investigated continuous treatment with a selective progesterone receptor modulator, ulipristal acetate (UPA), as a potential treatment for PMDD.

    Methods: The authors conducted an investigator-initiated, multicenter, double-blind, randomized, parallel-group clinical trial in which women with PMDD (N=95) were treated with either 5 mg/day of UPA or placebo during three 28-day treatment cycles. The primary outcome was the change in premenstrual total score on the Daily Record of Severity of Problems (DRSP) from baseline to end of treatment. DRSP scores were captured by daily ratings using a smartphone application and were analyzed with linear mixed models for repeated measures.

    Results: The mean improvement in DRSP score after 3 months was 41% (SD=18) in the UPA group, compared with 22% (SD=27) in the placebo group (mean difference 218%; 95% CI=229, 28). Treatment effects were also noted for the DRSP depressive symptom subscale (42% [SD=22] compared with 22% [SD=32]) and the DRSP anger/irritability subscale (47% [SD=21] compared with 23% [SD=35]), but not for the DRSP physical symptom subscale. Remission based on DRSP score was attained by 20 women in the UPA group (50.0%) and eight women in the placebo group (21.1%) (a statistically significant difference).

    Conclusions: If these results are replicated, UPA could be a useful treatment for PMDD, particularly for the psychological symptoms associated with the disorder.

  • 33.
    Dehara, Marina
    et al.
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital T2, Stockholm, Sweden.
    Kullberg, Susanna
    Respiratory Medicine Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Respiratory Medicine, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Sachs, Michael C.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
    Grunewald, Johan
    Respiratory Medicine Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Respiratory Medicine, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden.
    Arkema, Elizabeth V.
    Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital T2, Stockholm, Sweden.
    Menopausal hormone therapy and risk of sarcoidosis: a population-based nested case–control study in Sweden2024In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284Article in journal (Refereed)
    Abstract [en]

    Sarcoidosis incidence peaks in women between 50 and 60 years old, which coincides with menopause, suggesting that certain sex hormones, mainly estrogen, may play a role in disease development. We investigated whether menopausal hormone therapy (MHT) was associated with sarcoidosis risk in women and whether the risk varied by treatment type. We performed a nested case–control study (2007–2020) including incident sarcoidosis cases from the Swedish National Patient Register (n = 2593) and matched (1:10) to general population controls (n = 20,003) on birth year, county, and living in Sweden at the time of sarcoidosis diagnosis. Dispensations of MHT were obtained from the Swedish Prescribed Drug Register before sarcoidosis diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression. Ever MHT use was associated with a 25% higher risk of sarcoidosis compared with never use (aOR 1.25, 95% CI 1.13–1.38). When MHT type and route of administration were considered together, systemic estrogen was associated with the highest risk of sarcoidosis (aOR 1.51, 95% CI 1.23–1.85), followed by local estrogen (aOR 1.25, 95% CI 1.11–1.42), while systemic estrogen-progestogen combined was associated with the lowest risk compared to never users (aOR 1.12, 95% CI 0.96–1.31). The aOR of sarcoidosis did not differ greatly by duration of MHT use. Our findings suggest that a history of MHT use is associated with increased risk of sarcoidosis, with women receiving estrogen administered systemically having the highest risk.

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  • 34.
    Dubol, Manon
    et al.
    Department of Women's and Children's Health, Science for Life Laboratory, Uppsala University, Sweden.
    Stiernman, Louise
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Sundström-Poromaa, Inger
    Department of Women's and Children's Health, Uppsala University, Sweden.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Comasco, Erika
    Department of Women's and Children's Health, Science for Life Laboratory, Uppsala University, Sweden.
    Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder2024In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 355, p. 470-477Article in journal (Refereed)
    Abstract [en]

    Background: Premenstrual dysphoric disorder (PMDD) is hypothesized to stem from maladaptive neural sensitivity to ovarian steroid hormone fluctuations. Recently, we found thinner cortices in individuals with PMDD, compared to healthy controls, during the symptomatic phase. Here, we aimed at investigating whether such differences illustrate state-like characteristics specific to the symptomatic phase, or trait-like features defining PMDD.

    Methods: Patients and controls were scanned using structural magnetic resonance imaging during the mid-follicular and late-luteal phase of the menstrual cycle. Group-by-phase interaction effects on cortical architecture metrics (cortical thickness, gyrification index, cortical complexity, and sulcal depth) were assessed using surface-based morphometry.

    Results: Independently of menstrual cycle phase, a main effect of diagnostic group on surface metrics was found, primarily illustrating thinner cortices (0.3 < Cohen's d > 1.1) and lower gyrification indices (0.4 < Cohen's d > 1.0) in patients compared to controls. Furthermore, menstrual cycle-specific effects were detected across all participants, depicting a decrease in cortical thickness (0.4 < Cohen's d > 1.7) and region-dependent changes in cortical folding metrics (0.4 < Cohen's d > 2.2) from the mid-follicular to the late luteal phase.

    Limitations: Small effects (d = 0.3) require a larger sample size to be accurately characterized.

    Conclusions: These findings provide initial evidence of trait-like cortical characteristics of the brain of individuals with premenstrual dysphoric disorder, together with indications of menstrual cycle-related variations in cortical architecture in patients and controls. Further investigations exploring whether these differences constitute stable vulnerability markers or develop over the years may help understand PMDD etiology.

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  • 35.
    Dubol, Manon
    et al.
    Department of Women’s and Children’s Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Stiernman, Louise
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Wikström, Johan
    Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.
    Lanzenberger, Rupert
    Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
    Neill Epperson, C.
    Department of Psychiatry, Department of Family Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, CO, Aurora, United States.
    Sundström-Poromaa, Inger
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Comasco, Erika
    Department of Women’s and Children’s Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Differential grey matter structure in women with premenstrual dysphoric disorder: evidence from brain morphometry and data-driven classification2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 250Article in journal (Refereed)
    Abstract [en]

    Premenstrual dysphoric disorder (PMDD) is a female-specific condition classified in the Diagnostic and Statical Manual—5th edition under depressive disorders. Alterations in grey matter volume, cortical thickness and folding metrics have been associated with a number of mood disorders, though little is known regarding brain morphological alterations in PMDD. Here, women with PMDD and healthy controls underwent magnetic resonance imaging (MRI) during the luteal phase of the menstrual cycle. Differences in grey matter structure between the groups were investigated by use of voxel- and surface-based morphometry. Machine learning and multivariate pattern analysis were performed to test whether MRI data could distinguish women with PMDD from healthy controls. Compared to controls, women with PMDD had smaller grey matter volume in ventral posterior cortices and the cerebellum (Cohen’s d = 0.45–0.76). Region-of-interest analyses further indicated smaller volume in the right amygdala and putamen of women with PMDD (Cohen’s d = 0.34–0.55). Likewise, thinner cortex was observed in women with PMDD compared to controls, particularly in the left hemisphere (Cohen’s d = 0.20–0.74). Classification analyses showed that women with PMDD can be distinguished from controls based on grey matter morphology, with an accuracy up to 74%. In line with the hypothesis of an impaired top-down inhibitory circuit involving limbic structures in PMDD, the present findings point to PMDD-specific grey matter anatomy in regions of corticolimbic networks. Furthermore, the results include widespread cortical and cerebellar regions, suggesting the involvement of distinct networks in PMDD pathophysiology.

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  • 36.
    Gu, Xuan
    et al.
    Department of Neuroscience, Science for Life Laboratory, Uppsala University, Sweden.
    Dubol, Manon
    Department of Neuroscience, Science for Life Laboratory, Uppsala University, Sweden.
    Stiernman, Louise
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Wikström, Johan
    Department of Surgical Sciences, Neuroradiology, Uppsala University, Sweden.
    Hahn, Andreas
    Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
    Lanzenberger, Rupert
    Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria.
    Epperson, C. Neill
    Department of Psychiatry, University of Colorado School of Medicine, USA.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Sundström-Poromaa, Inger
    Department of Women’s and Children’s Health, Uppsala University, Sweden.
    Comasco, Erika
    Department of Neuroscience, Science for Life Laboratory, Uppsala University, Sweden.
    White matter microstructure and volume correlates of premenstrual dysphoric disorder2022In: Journal of Psychiatry & Neuroscience, ISSN 1180-4882, E-ISSN 1488-2434, Vol. 47, no 1, p. E67-E76Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by psychological and physical symptoms. Differences in white matter have been associated with affective and anxiety disorders, which share some symptoms with PMDD. However, whether white matter structure differs between the brains of individuals with PMDD and healthy controls is not known, nor is its relation to symptom severity.

    METHODS: We performed tract-based spatial statistics and voxel-based morphometry analyses of diffusion tensor imaging metrics and white matter volume, using 2 neuroimaging data sets (n = 67 and n = 131) and a combined whole-brain and region-of-interest approach. We performed correlation analyses to investigate the relationship between regions with different white matter microstructure and volume and PMDD symptom severity.

    RESULTS: We found greater fractional anisotropy in the left uncinate fasciculus (d = 0.69) in individuals with PMDD compared to controls. Moreover, the volume of the right uncinate fasciculus was higher in individuals with PMDD compared to controls (d = 0.40). As well, the severity of premenstrual depression was positively correlated with fractional anisotropy in the right superior longitudinal fasciculus (r = 0.35).

    LIMITATIONS: It is challenging to interpret group differences in diffusion tensor imaging metrics in terms of their underlying biophysical properties. The small size of the control group in the diffusion tensor imaging study may have prevented effects of interest from being detected.

    CONCLUSION: The findings of the present study provide evidence of differential cerebral white matter structure associated with PMDD and its symptoms.

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  • 37. Hagen Ernst, Emil
    et al.
    Holopainen, Elina
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Stages of puberty2020In: Obstetrics and Gynecology: online textbook for medical students, Århus: Nordic Federation of Societies of Obstetrics and Gynecology , 2020Chapter in book (Other academic)
  • 38.
    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.

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  • 39.
    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)
  • 40.
    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.

  • 41.
    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)
  • 42.
    Holmberg, Ellinor