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  • 1.
    Ahangari, Alebtekin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå Neurosteroid Research Center, Umeå University, Umeå, Sweden.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå Neurosteroid Research Center, Umeå University, Umeå, Sweden.
    Innala, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå Neurosteroid Research Center, Umeå University, Umeå, Sweden.
    Andersson, C.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå Neurosteroid Research Center, Umeå University, Umeå, Sweden.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå Neurosteroid Research Center, Umeå University, Umeå, Sweden.
    Acute intermittent porphyria symptoms during the menstrual cycle2015In: Internal medicine journal (Print), ISSN 1444-0903, E-ISSN 1445-5994, Vol. 45, no 7, p. 725-731Article in journal (Refereed)
    Abstract [en]

    Background: Acute intermittent porphyria (AIP), a life-threatening form of the disease, is accompanied by several pain, mental and physical symptoms.

    Aims: In this study, we evaluated the cyclicity of AIP and premenstrual syndrome (PMS) symptoms in 32 women with DNA-diagnosed AIP during their menstrual cycles, in northern Sweden.

    Methods: The cyclicity of AIP symptoms and differences in them between the follicularand luteal phases, and the cyclicity of each symptom in each individual woman indifferent phases of her menstrual cycle were analysed with a prospective daily ratingquestionnaire. PMS symptoms were also evaluated in the patients on a daily rating scale.

    Results: Of the 32 women, 30 showed significant cyclicity in at least one AIP or PMS symptom (P < 0.05–0.001). Back pain (10/32) was the most frequent AIP pain symptomand sweet craving (10/15) was the most frequent PMS symptom. Pelvic pain (F = 4.823,P = 0.036), irritability (F = 7.399, P = 0.011), cheerfulness (F = 5.563, P = 0.025), sexualdesire (F = 8.298, P = 0.007), friendliness (F = 6.157, P = 0.019), breast tenderness (F =21.888, P = 0.000) and abdominal swelling (F = 16.982, P = 0.000) showed significantcyclicity. Pelvic pain and abdominal swelling (rs= 0.337, P < 0.001) showed the strongest correlation. The age of women with latent AIP was strongly correlated with abdominal swelling during the luteal phase (rs= 0.493, P < 0.01).

    Conclusion: Our results suggest that the symptoms of AIP patients change during their menstrual cycles.

  • 2.
    Andersson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Innala, Eva
    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.
    Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden2003In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 254, no 2, p. 176-183Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe the clinical expression of acute intermittent porphyria (AIP) in women, their use of exogenous sex hormones, and the effects on AIP. DESIGN: A retrospective population-based study. SUBJECTS: All women aged > or =18 years (n = 190) with DNA-diagnosed AIP in northern Sweden. RESULTS: A total of 166 women (87%) participated; 91 (55%) had manifest AIP. Severe attacks were reported by 82%; 39% reported recurrent premenstrual AIP attacks and 22% reported chronic AIP symptoms. Oral hormonal contraceptives had been used by 58% of all these women and by 50 with manifest AIP (57%). Twelve women (24%) associated oral contraceptives as precipitating AIP attacks; in nine cases their first attack. One woman experienced relief from AIP symptoms. On commencing their treatment, 72% of the women with manifest AIP had not yet suffered their first attack. Twenty-two women (25%) aged > or =45 years had used hormonal replacement therapy (HRT) at menopause to remedy climacteric symptoms (the percutaneous route was most frequently used); no AIP attack was precipitated. HRT to remedy vaginal dryness was used by 26 women (28%) aged > or =45 years without triggering an AIP attack. Miscarriages were more frequent in women with manifest AIP (50%) than in the latent group (30%, P = 0.014). CONCLUSIONS: About half of the women with AIP had used oral hormonal contraceptives. As 25% of women with manifest AIP reported attacks associated with such drugs, caution must still be recommended. Menopausal HRT only rarely affected the disorder. Miscarriage was more common amongst women with manifest AIP.

  • 3.
    Andersson, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Nilsson, T.
    From the Primary Health Care Centre, Arvidsjaur, Sweden, .
    Bäckström, Torbjörn
    Atypical attack of acute intermittent porphyria: paresis but not abdominal pain2002In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 252, no 3, p. 265-270Article in journal (Refereed)
    Abstract [en]

    We report a case of acute intermittent porphyria (AIP) in a 45-year-old woman. Her first attack occurred at the age of 38. Because of escalating cyclical premenstrual attacks, the following 2 years, depletion of the endogenous sex hormone was considered as haeme arginate treatment proved insufficient. Gonadotropin releasing hormone agonist treatment with low-dose oestradiol add back was quite successful initially but was abandoned after 18 months when progesterone add back precipitated a severe attack. Following hysterectomy and oophorectomy at age 42 and oestradiol add back, a remarkable monthly regularity of attacks ensured periodically but with milder symptoms. Two years after surgery, preceded by six attack-free months, a puzzling symptom-shift occurred, from abdominal pain, back and thigh pain during the attacks, to solely severe distal extensor paresis in the arms. Haeme arginate treatment interrupted the progress of the paresis almost immediately and motor function improved considerably up to the 9-month follow-up. Electrophysiological examination revealed only motor neuropathy, consistent with axonal degeneration. Subsequently the symptoms changed yet again, to sensory disturbances with numbness and dysesthesia as the primary expression followed by rather mild abdominal pain. However, cyclical attacks occurred, despite absence of endogenous ovarial hormone production, possibly attributable to impaired oestrogen metabolism in the liver, or adrenal oestrogen production. Treatment comprising oophorectomy, low-dose oestradiol add back and haeme arginate infusion for 2 days on the appearance of early AIP symptoms is now quite successful affording improvement in life quality.

  • 4.
    Andersén, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Damber, Jan-Erik
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hjemdahl, Paul
    Korsgren, Olle
    Olsson, Håkan
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Svensk medicinsk forskning behöver inte mer styrning2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 22-23, p. 980-981Article in journal (Other (popular science, discussion, etc.))
  • 5.
    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)
  • 6.
    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.

  • 7.
    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)
  • 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.
    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)
  • 9.
    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)
  • 10.
    Appelblad, Patrik
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry. Faculty of Medicine, Clinical Sciences.
    Ahmed, Abdu
    Umeå University, Faculty of Science and Technology, Chemistry.
    Pontén, Einar
    Umeå University, Faculty of Science and Technology, Chemistry.
    Bäckström, Torbjörn
    Faculty of Medicine, Clinical Sciences.
    Irgum, Knut
    Umeå University, Faculty of Science and Technology, Chemistry.
    Perfluorosulfonated Ionomer-Modified Polyethylene. A Material for Simultaneous Solid-Phase Enrichment and Enhanced Precolumn Dansylation of C-21 Ketosteroids in Human Serum2001In: Analytical Chemistry, Vol. 73, no 15, p. 3701-8Article in journal (Refereed)
    Abstract [en]

    A new derivatization procedure has been developed where solid-phase catalysis is utilized to facilitate the formation of hydrazones in precolumn labeling of keto-containing compounds. This procedure has been implemented on a solid-phase enrichment and enhanced derivatization (SPEED) device, prepared from porous polyethylene that has been coated with Nafion and dansylhydrazine. The SPEED devices have been optimized using experimental design and characterized for dansylation of C-21 ketosteroids by multivariate data analysis, using progesterone as the model compound. The reaction temperature and the molar ratio between the steroid and the derivatization reagent were found to be the factors most strongly affecting the reaction. Faster reaction kinetics were achieved when the molar ratio between dansylhydrazine and the steroid was increased. Mass spectroscopic analysis showed that the four derivative peaks eluting when derivatized progesterone was separated on an octadecyl silica stationary phase were due to the syn and anti mono- and bis(hydrazones) formed in the reaction. Using optimal reaction conditions, the derivatives mainly constitute the syn and anti conformers of bis-derivatives. In contrast to solution-based acid catalysis, the SPEED device was remarkably insensitive to water in the reaction mixture. A sample volume of 400 L was found to be the maximum, enabling sample enrichment prior derivatization. Using optimal experimental conditions, picomole amounts of ketosteroids could be derivatized in 10 min at room temperature. Analysis of spiked serum samples containing 0.4-2.0 nmol of progesterone showed overall recoveries of 52-63%. The corresponding 3 detection limit was 1.3 pmol (n = 4, 100 L injected), as estimated from calibration curve data.

  • 11.
    Appelblad, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jonsson, Tobias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Irgum, Knut
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Determination of C-21 ketosteroids in serum using trifluoromethanesulfonic acid catalyzed precolumn dansylation and 1,1’-oxalyldiimidazole postcolumn peroxyoxalate chemiluminescence detection1998In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 70, no 23, p. 5002-5009Article in journal (Refereed)
    Abstract [en]

    A new procedure for the quantitation of C-21 ketosteroids using trifluoromethanesulfonic acid-catalyzed precolumn dansylation and coupled column liquid chromatographic separation, followed by postcolumn 1,1‘-oxalyldiimidazole peroxyoxalate chemiluminescence detection is presented. In the simultaneous optimization of chromatographic resolution and chemiluminescence intensity, a coupled column chromatographic system and a stopped-flow system were used. An eluent containing 20 mM phosphate buffer at pH 6.7 accomplished an efficient separation of 3α-hydroxy-5β-pregnan-20-one from a mixture containing 10 C-21 ketosteroids. Phosphate buffer also proved to be the most advantageous, among the six buffers tested, for sensitive detection. Experimental design and multivariate data analysis were used to characterize and optimize the postcolumn reaction chemistry in the chromatographic system. A valid full factorial design with excellent predictability showed that the flow rates for both 1,1‘-oxalyldiimidazole and hydrogen peroxide were the factors most strongly affecting the sensitivity of the system. The theoretical plate numbers were above 11 000 for all 10 dansylated ketosteroids. The 3σ detection limit estimated from 3α-hydroxy-5β-pregnan-20-one calibration curve data was 1.6 pmol (n = 4, 125 μL injected) and spiked serum containing 0−74 pmol of this compound showed overall recoveries of 73 ± 9% (n = 12). Quantitation of 3α-hydroxy-5β-pregnan-20-one was finally carried out on 45 serum samples and the results compared to those from a radioimmunoassay (RIA) method. The data acquired with the procedure described in this work compare well with the results from RIA, which confirms the reliability of the new analytical procedure.

  • 12. Bannbers, Elin
    et al.
    Gingnell, Malin
    Engman, Jonas
    Morell, Arvid
    Sylven, Sara
    Skalkidou, Alkistis
    Kask, Kristiina
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wikstrom, Johan
    Poromaa, Inger Sundstrom
    Prefrontal activity during response inhibition decreases over time in the postpartum period2013In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 241, p. 132-138Article in journal (Refereed)
    Abstract [en]

    The postpartum period is characterized by complex hormonal changes, but human imaging studies in the postpartum period have thus far predominantly focused on the neural correlates of maternal behavior or postpartum depression, whereas longitudinal studies on neural correlates of cognitive function across the postpartum period in healthy women are lacking. The aim of this study was to longitudinally examine response inhibition, as a measure of executive function, during the postpartum period and its neural correlates in healthy postpartum women and non-postpartum controls. Thirteen healthy postpartum women underwent event-related functional magnetic resonance imaging while performing a Go/NoGo task. The first assessment was made within 48 h of delivery, and the second at 4-7 weeks postpartum. In addition, 13 healthy women examined twice during the menstrual cycle were included as non-postpartum controls. In postpartum women region of interest analyses revealed task-related decreased activations in the right inferior frontal gyrus, right anterior cingulate, and bilateral precentral gyri at the late postpartum assessment. Generally, postpartum women displayed lower activity during response inhibition in the bilateral inferior frontal gyri and precentral gyri compared to non-postpartum controls. No differences in performance on the Go/NoGo task were found between time-points or between groups. In conclusion, this study has discovered that brain activity in prefrontal areas during a response inhibition task decreases throughout the course of the first postpartum weeks and is lower than in non-postpartum controls. Further studies on the normal adaptive brain activity changes that occur during the postpartum period are warranted. (C) 2012 Elsevier B.V. All rights reserved.

  • 13.
    Bengtsson, Sara
    et al.
    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.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nitsch, Roger
    University of Zürich, Division of Psychiatry Research and Psychogeriatric Medicine,.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models2013In: Current Alzheimer Research, ISSN 1567-2050, Vol. 10, no 1, p. 38-47Article in journal (Refereed)
    Abstract [en]

    Abstract: Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Aβ in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels. learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Ab in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels.

  • 14.
    Bengtsson, Sara K.
    et al.
    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.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nitsch, Roger M.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Brief but Chronic Increase in Allopregnanolone Cause Accelerated AD Pathology Differently in Two Mouse Models2013In: Current Alzheimer Research, ISSN 1567-2050, Vol. 10, no 1, p. 38-47Article in journal (Refereed)
    Abstract [en]

    Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABA(A) receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABA(A) receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer's disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble A beta in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased A beta-levels caused by mildly elevated ALLO-levels.

  • 15.
    Bengtsson, Sara K.
    et al.
    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.
    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.
    Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 1, p. 71-84Article in journal (Refereed)
    Abstract [en]

    The endogenous neurosteroid allopregnanolone alters neuronal excitability via modulation of the GABA(A) receptor and causes decreased neurotransmission. In Alzheimer's disease (AD), neurotransmission seems to alter the levels of toxic intracellular amyloid-beta (A beta) oligomers, which are implicated in AD pathogenesis and cause cognitive decline. Inhibition of synaptic activity has been shown to increase levels of intracellular A beta. Allopregnanolone at endogenous stress levels inhibits synaptic activity and could have similar effects. By using a transgenic A beta PP(Swe)PSEN1(Delta E9) mouse model for AD, we observed that chronic allopregnanolone treatment for three months with stress levels of allopregnanolone impaired learning in the Morris water maze. The learning impairment was seen one month after the end of treatment. Chronic allopregnanolone treatment also led to increased levels of soluble A beta in the brain, which could be a sign of advanced pathogenesis. Since the learning and memory of wild-type mice was not affected by the treatment, we propose that chronic allopregnanolone treatment accelerates the pathogenesis of AD. However, further studies are required in order to determine the underlying mechanism.

  • 16.
    Bengtsson, Sara K S
    et al.
    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. Umecrine Cognit AB, Umea, Sweden.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Long-term continuous allopregnanolone elevation causes memory decline and hippocampus shrinkage, in female wild-type B6 mice2016In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 78, p. 160-167Article in journal (Refereed)
    Abstract [en]

    Chronic stress in various forms increases the risk for cognitive dysfunction, dementia and Alzheimer's disease. While the pathogenesis behind these findings is unknown, growing evidence suggests that chronic increase in neurosteroid levels, such as allopregnanolone, is part of the mechanism. We treated wild-type C57BL/6J mice with allopregnanolone for 5months, using osmotic pumps. This treatment led to moderately increased levels of allopregnanolone, equivalent to that of mild chronic stress. After an interval of no treatment for 1month, female mice showed impaired learning and memory function in the Morris water maze (MWM) in combination with diminished hippocampus weight and increased cerebellum weight, both correlating to MWM performance. Male mice showed a minor reduction in memory function and no differences in brain structure. We conclude that chronic allopregnanolone elevation can lead to cognitive dysfunction and negative brain alterations. We suggest that allopregnanolone could play a key role in the pathogenesis of stress-induced cognitive disturbances and perhaps dementia.

  • 17.
    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.

  • 18.
    Bengtsson, Sara
    et al.
    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.
    Gouissem, Samira
    Umecrine AB.
    Johansson, Maja
    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.
    Chronic allopregnanolone elevation cause altered plaque production in Swe/PS1 miceManuscript (preprint) (Other academic)
    Abstract [en]

    Abstract. We have previously shown that chronic elevation of the neurosteroid allopregnanolone caused learning dysfunction and increased levels of soluble Aβ in the Swe/PS1 mouse model. The mechanism behind these findings is however unknown. We further investigated the brain tissue of these mice to identify any effects on congophilic plaque burden, Aβ42-specific plaque burden and synaptic function. We found a significant reduction in the average size of the congophilic core of neuritic plaques after chronic allopregnanolone treatment compared to vehicle. This seems to be caused by an altered plaque production, leading to more abundant, but smaller neuritic plaques. We may also have detected a decrease in the amount of synaptophysin, and thus synaptic function among the same mice. However, the long interval between the end of treatment and tissue collection possibly allowed time for recovery and only minor differences were noted. We found that the natural relationship between levels of insoluble Aβ, congophilic and Aβ42-specific plaque load was disrupted after chronically elevated allopregnanolone levels. Furthermore, the levels of syn-aptophysin and insoluble Aβ became more important in the relationship to learning and memory. The causality of these factors is still unknown and further studies are required to fully understand the effect of neurosteroids on AD development.

  • 19.
    Birzniece, Vita
    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.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    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.
    Löfgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ragagnin, Gianna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Taube, Magdalena
    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 Pharmacology and Clinical Neuroscience, Pharmacology.
    Wang, Ming-De
    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.
    Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems.2006In: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 51, no 2, p. 212-239Article in journal (Refereed)
  • 20.
    Birzniece, Vita
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, I-M
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, MD
    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.
    Olsson, T
    Ovarian hormone effects on 5-hydroxytryptamine (2A) and 5-hydroxytryptamine (2C) receptor mRNA expression in the ventral hippocampus and frontal cortex of female rats.2002In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 319, no 3, p. 157-161Article in journal (Refereed)
    Abstract [en]

    Alterations in female gonadal hormones are associated with anxiety and mood changes. The aim of the present study was to determine influences of chronic gonadal hormone supplementation on 5-HT(2A) and 5-HT(2C) receptor mRNA levels in the ventral hippocampus and the frontal cerebral cortex. Ovariectomized adult female Sprague-Dawley rats (n=37) received implantation of subcutaneous pellets containing different dosages of 17beta-estradiol alone or in combination with progesterone, or placebo pellets, for 2 weeks. Serotonin receptor mRNA levels were analyzed by in situ hybridization in the ventral hippocampus and 5-HT(2A) receptor mRNA also in the frontal cortex. Estradiol treatment in combination with low-dose progesterone increased 5-HT(2A) receptor mRNA by 43% in the CA2 region of the ventral hippocampus, while estradiol combined with high-dose progesterone increased the expression of this gene by 84% in ventral CA1. 5-HT(2A) mRNA expression in the frontal cortex was not influenced by hormone manipulation. 5-HT(2C) receptor gene expression was in the ventral hippocampus decreased in the CA2, ventral CA1 and the subiculum subregions by high-dose estradiol treatment (8-20% decreases). Effects on mood by gonadal hormones can be mediated, at least partly, through influences on 5-HT(2A) and 5-HT(2C) receptor expression.

  • 21.
    Birzniece, Vita
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, I-M
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, MD
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Seckl, JR
    Bäckström, T
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Olsson, T
    Serotonin 5-HT(1A) receptor mRNA expression in dorsal hippocampus and raphe nuclei after gonadal hormone manipulation in female rats.2001In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 74, no 2, p. 135-142Article in journal (Refereed)
    Abstract [en]

    Female ovarian steroids influence mood and cognition, an effect presumably mediated by the serotonergic system. A key receptor in this interplay may be the 5-HT(1A) receptor subtype. We gave adult ovariectomized female rats subcutaneous pellets containing different dosages of 17 beta-estradiol alone or in combination with progesterone, or placebo pellets, for 2 weeks. 5-HT(1A) receptor mRNA levels were analyzed by in situ hybridization in the dorsal hippocampus, dorsal and median raphe nuclei, and entorhinal cortex. Estradiol treatment alone reduced 5-HT(1A) gene expression in the dentate gyrus and the CA2 region (17 and 19% decrease, respectively). Estradiol combined with progesterone supplementation increased 5-HT(1A) gene expression versus placebo in the CA1 and CA2 subregions of the dorsal hippocampus (16 and 30% increase, respectively). Concomitantly, 5-HT(1A) mRNA expression was decreased by 13% in the ventrolateral part of the dorsal raphe nuclei, while no changes were found in the median raphe nucleus and entorhinal cortex. Chronic effects of ovarian hormones on 5-HT(1A) receptor mRNA expression appear tissue-specific and involve hippocampal subregions and the raphe nuclei. Modulation of 5-HT(1A) receptor gene expression may be of importance for gonadal steroid effects on mood and cognition. Copyright 2001 S. Karger AG, Basel

  • 22.
    Birzniece, Vita
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Türkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    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.
    Johansson, Inga-Maj
    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.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    GABA(A) receptor changes in acute allopregnanolone tolerance2006In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 535, no 1-3, p. 125-134Article in journal (Refereed)
    Abstract [en]

    To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.

  • 23.
    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.

  • 24.
    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.

  • 25.
    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.

  • 26.
    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.

  • 27.
    Björn, Inger
    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.
    Drug related negative side effects is a common reason for poor compliance in hormone replacement therapy1999In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 32, no 2, p. 77-86Article in journal (Refereed)
    Abstract [en]

    Objectives: The reasons for poor compliance with hormone replacement therapy (HRT) and, in particular drug-related reasons, have not yet been fully elucidated. In this study, a cohort of peri- or postmenopausal women—mainly workers from a small town and surrounding rural area—was studied. The aim of the study was to investigate why some women never start or discontinue HRT, even when great effort has been made to inform and fulfill the demands of the patient. Methods: All women who were given a HRT prescription at a gynecological practice between September 1991 and December 1992 participated in a longitudinal study. A written questionnaire was mailed to these patients in 1996. Data from the questionnaire was supplemented with information from the medical records. Care of patients included initial information, follow-up within 4 months, yearly visits supplemented with contacts on demand. Results: 356 women received the questionnaire, among which 92% replied. A total of 2% never started HRT. Seventy-five percent continued the therapy for more than 3 years. Reasons for discontinuing HRT were negative side-effects (35%), desire to find out if climacteric symptoms had ended (26%), fear of cancer and thrombosis (25%), weariness of bleeding (19%) and a wish to deal with the problems ‘naturally’ (15%). Conclusions: Compliance with HRT can be high if adequate information is given and follow-ups are made. The main reason for poor compliance was negative side-effects, most likely progestin-related. The results of this study suggest that the future challenge will be to minimize negative side-effects of HRT.

  • 28.
    Björn, Inger
    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.
    Lalos, Ann
    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.
    Adverse mood effects during postmenopausal hormone treatment in relation to personality traits.2006In: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 9, no 4, p. 290-297Article in journal (Refereed)
  • 29.
    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.

  • 30.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Plasma estrogen and progesterone in relation to premenstrual tension and catamenial epilepsy1976Doctoral thesis, comprehensive summary (Other academic)
  • 31.
    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)
  • 32.
    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.

  • 33.
    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.

  • 34.
    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.

  • 35.
    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.

  • 36.
    Bäckström, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Haage, D.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, I. M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strömberg, J.
    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.
    Andreen, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ossewaarde, L.
    van Wingen, G. A.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bengtsson, S. K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons2011In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 191, no Special issue, p. 46-54Article, review/survey (Refereed)
    Abstract [en]

    Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane C1(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. (C) 2011 Published by Elsevier Ltd on behalf of IBRO.

  • 37.
    Bäckström, Torbjörn
    et al.
    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. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Wahlström, Kerstin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Wang, Ming-De
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Isoallopregnanolone; an antagonist to the anaesthetic effect of allopregnanolone in male rats2005In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 512, no 1, p. 15-21Article in journal (Refereed)
    Abstract [en]

    The interaction of isoallopregnanolone (3β-OH-5α-pregnan-20-one) on allopregnanolone (3α-OH-5α-pregnan-20-one) induced anaesthesia was studied in male rats using burst suppression of 1 s (“silent second”) with an electroencephalographic-threshold method. The i.v. administration of isoallopregnanolone was varied in relation to induction of “silent second”. Pre-treatment with isoallopregnanolone (12.5–50 mg/kg iv) 2 min prior to the threshold test gave an increase in the threshold dose of allopregnanolone(ANOVA df(3;36), F=13.61, P<0.001), which was dose dependent (r=0.73, b [slope]=0.08, df=38, P<0.001). After isoallopregnanolone pre-treatment, but not in the controls, anaesthesia time was positively related to the dose of allopregnanolone (r=0.52, b=1.72, df=28,P<0.01). Anaesthesia times were not influenced by a corresponding administration of isoallopregnanolone immediately after induction of “silent second”. When allopregnanolone and isoallopregnanolone were infused together at molar ratios of 1:1, 1:1.23, 1:1.43, a linear increase of the threshold doses of allopregnanolone was seen in relation to the dose of isoallopregnanolone (r=0.86, b=0.40, df=8,P<0.01). Thus isoallopregnanolone can antagonise the anaesthetic action of allopregnanolone.

     

  • 38.
    Dahmoun, Marju
    et al.
    Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
    Boman, Karin
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Cajander, S
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
    Intratumoral effects of medroxy-progesterone on proliferation, apoptosis, and sex steroid receptors in endometrioid endometrial adenocarcinoma2004In: Gynecol Oncol, ISSN 0090-8258, Vol. 92, no 1, p. 116-126Article in journal (Refereed)
  • 39.
    Dahmoun, Marju
    et al.
    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.
    Risberg, Björn
    Karlsson, Mats G
    Pavlenko, Tatjana
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Apoptosis, proliferation, and sex steroid receptors in postmenopausal endometrium before and during HRT.2004In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 49, no 2, p. 114-123Article in journal (Refereed)
  • 40.
    Dennerstein, Lorraine
    et al.
    Department of Psychiatry, The University of Melbourne, Victoria, Australia.
    Lehert, Philippe
    Department of Psychiatry, The University of Melbourne, Victoria, Australia.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Heinemann, Klaas
    Bayer Schering Pharma, Women's Health Care, Berlin, Germany.
    Premenstrual symptoms - severity, duration and typology: an international cross-sectional study2009In: Menopause international, ISSN 1754-0453, Vol. 15, no 3, p. 120-126Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Determine women's experiences of premenstrual symptoms. STUDY DESIGN: Cross-sectional survey. Sample In all, 4085 women aged 14-49 years recruited by random telephone digit dialing in France, Germany, Hungary, Italy, Spain, UK, Brazil and Mexico. Main outcome measures Telephone interview checklist of 23 premenstrual symptoms, sociodemographic variables and lifestyle variables. RESULTS: The most prevalent symptoms were abdominal bloating, cramps or abdominal pain, breast tenderness, irritability and mood swings. Severity of symptoms is directly proportional to duration (R = 0.79). Hierarchical clustering found the following mental and physical domains and a typology: 'Mild' type (40.8%) with minimal symptoms; 'Moderate M' type (28.7%) with moderately severe, mostly mental symptoms; 'Moderate P' type (21.9%) with moderately severe, mostly physical symptoms; and 'Severe' type (8.6%) with severe intensity of both mental and physical symptoms. Multiple stepwise regression found significant effects on symptom duration severity index of age (linear and quadratic effects), current smoking and country. CONCLUSIONS: Further research is needed on the impact of premenstrual symptoms on quality of life, and whether a brief symptom list could be developed as a valid and reliable tool globally.

  • 41.
    Dennerstein, Lorraine
    et al.
    Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
    Lehert, Philippe
    Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Heinemann, Klaas
    Women's Health Care, Bayer Schering Pharma, Berlin, Germany.
    The effect of premenstrual symptoms on activities of daily life2010In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 94, no 3, p. 1059-1064Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess impact of premenstrual symptoms on activities of women's daily lives (ADL). DESIGN: Cross-sectional population-based survey. SETTING: Market research company. PATIENT(S): A total of 4,085 women aged 14-50 years recruited by random telephone digit dialing in France, Germany, Hungary, Italy, Spain, the United Kingdom, Brazil, and Mexico. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A telephone interview checklist of 23 premenstrual symptoms, sociodemographic and lifestyle variables, and ADL effects (global question and seven areas). Stepwise regression measured the effect of premenstrual symptoms and sociodemographic factors on ADL. RESULT(S): Symptoms and symptom domains (physical and mental) had similar negative effects on ADL. Activities of daily life were predominantly affected by symptom severity. Income level, age, and country also significantly affected ADL. In all, 2,638 women (64.6%) were minimally affected in ADL, 981 (24%) were moderately affected, and 454 (11.1%) were severely affected. CONCLUSION(S): Both physical and mental premenstrual symptoms have significant impact on quality of life, assessed as ADL. Up to 35% of women of reproductive age in Europe and Latin America were moderately or severely affected in ADL by cyclical premenstrual symptoms.

  • 42. Droogleever Fortuyn, Hal A
    et al.
    van Broekhoven, Frank
    Span, Paul N
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
    Zitman, Frans G
    Verkes, Robbert J
    Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density.2004In: Psychoneuroendocrinology, ISSN 0306-4530, Vol. 29, no 10, p. 1341-4Article in journal (Refereed)
  • 43. Ekenros, Linda
    et al.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Hirschberg, Angelica Lindén
    Fridén, Cecilia
    Changes in premenstrual symptoms in women starting or discontinuing use of oral contraceptives2019In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 35, no 5, p. 422-426Article in journal (Refereed)
    Abstract [en]

    It is not clear whether oral contraceptive (OC) treatment affects premenstrual symptoms in women. The aim of the present study was to evaluate changes in premenstrual symptoms (PMS) in women starting to use or discontinuing the use of OCs. Twenty-four healthy women with no previous diagnosis of premenstrual dysphoric disorder were included in this study with a prospective crossover design. Nineteen women completed daily ratings of somatic and mood symptoms during two hormonally different cycles, during a normal menstrual cycle and while using OCs. The menstrual cycle phases were hormonally verified and the low-dose, monophasic OCs were used in a 21/7 regimen. The onset of OC use significantly decreased premenstrual somatic symptoms, but it did not affect mood symptoms. In the women who discontinued OC use, no significant changes in neither somatic nor mood symptoms appeared in the premenstrual phase.

  • 44. Ekenros, Linda
    et al.
    Hirschberg, Angelica Lindén
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Fridén, Cecilia
    Postural control in women with premenstrual symptoms during oral contraceptive treatment2011In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 90, no 1, p. 97-102Article in journal (Refereed)
    Abstract [en]

    Objective. This study investigates postural control among women with and without premenstrual symptoms (PMS) on oral contraceptive (OC) treatment. Design. Prospective repeated measures design. Setting. Women's health clinical research unit at a university hospital.

    Population. Fifteen women using low-dose monophasic oral contraceptives participated in the study. Depending on premenstrual symptoms, the women were divided into one PMS group and one non-PMS group.

    Methods. Postural control (displacement area) was measured using an AMTI® force platform during the active hormone phase (OC phase) and the hormone-free phase (non-OC phase) of the pill chart. Premenstrual symptoms were evaluated prospectively using the Cyclicity Diagnoser.

    Main Outcome Measures. Displacement area as a measure of postural control.

    Results. Six of 15 women showed premenstrual symptoms (primarily negative mood symptoms) between the phases and were considered having premenstrual symptoms. When analyzing postural control, the PMS group displayed a significantly greater displacement area in the OC-phase compared to the non-OC phase. In contrast, the non-PMS group did not show any significant difference between the phases. Furthermore, the PMS group had significantly greater displacement area during the OC phase compared to the non-PMS group.

    Conclusions. The present study shows that women with premenstrual symptoms have greater displacement area than those without premenstrual symptoms during the active phase of oral contraceptive treatment. Negative mood symptoms may affect the maintenance of postural control by central interactions. Further studies are needed to clarify the precise mechanism for altered postural control in women with premenstrual symptoms.

  • 45.
    Ekholm, Ulla-Britt
    et al.
    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.
    Hammarbäck, Stefan
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckstrom, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sexuality and androgens in women with cyclical mood changes and pre-menstrual syndrome2014In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 93, no 3, p. 248-255Article in journal (Refereed)
    Abstract [en]

    Objective To study the relation between androgen levels and sexual interest in women with different kinds of pre-menstrual syndrome (PMS). Design Causal comparative study. Setting Swedish university hospital outpatient clinic. Population Seventy women with cyclical mood changes. Methods Pre-menstrual syndrome patients were divided into those with and those without preovulatory symptoms. In 37 women, early follicular phase blood samples were analyzed for androstenedione, testosterone, sex hormone-binding globulin (SHBG), progesterone and estradiol, using radioimmunoassay. The participants were divided into subgroups depending on whether the levels of androgens and SHBG were above or below the median. In 33 of them it was possible to compare the cyclicity in sexual parameters between these subgroups. Main outcome measures Daily ratings of sexual parameters and hormonal analyses. Results Plasma testosterone was significantly lower and SHBG significantly higher in women with luteal phase symptoms compared with those with additional follicular phase symptoms. ANOVA showed significant cyclicity for all sexual parameters consistently. For the “sexual feelings” and “pleasant sexual thoughts” parameters, cyclicity was the same whether or not the hormonal levels were “high” or “low.” Conclusions The “Pure-PMS” group and the “pre-menstrual-exacerbation” groups differed in their androgen and SHBG levels. Women suffering from PMS with higher neuroticism Eysenck Personality Inventory scores or “low” levels of androgens and SHBG would be more likely to have a decreased sexual interest pre-menstrually than would women with a high level.

  • 46. Eriksson, Olle
    et al.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
    Stridsberg, Mats
    Hammarlund-Udenaes, Margareta
    Naessén, Tord
    Differential response to estrogen challenge test in women with and without premenstrual dysphoria.2006In: Psychoneuroendocrinology, ISSN 0306-4530, Vol. 31, no 4, p. 415-27Article in journal (Refereed)
  • 47.
    Haage, David
    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.
    Johansson, Staffan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Interaction between allopregnanolone and pregnenolone sulfate in modulating GABA-mediated synaptic currents in neurons from the rat medial preoptic nucleus.2005In: Brain Research, ISSN 0006-8993, Vol. 1033, no 1, p. 58-67Article in journal (Refereed)
    Abstract [en]

    The two neurosteroids 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone; AlloP) and pregnenolone sulfate (PregS) affect neuronal GABA(A) receptors differently. While AlloP mainly potentiates the currents through GABA(A) receptors, PregS reduces such currents. The present study aimed at clarifying the interaction of AlloP and PregS at GABA(A) receptors in neurons from the medial preoptic nucleus of male rat. AlloP has previously been shown to dramatically prolong GABA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in these neurons. Here, by recording sIPSCs under voltage-clamp conditions with the perforated-patch technique, it was shown that PregS by itself did not significantly affect the amplitude or time course of such currents. However, PregS, in a concentration-dependent manner, reduced the AlloP-evoked prolongation of sIPSC decay when the two neurosteroids were applied together. In contrast to sIPSC amplitude and time course, sIPSC frequency was significantly reduced by 10 microM PregS alone. Further, although 1.0 microM AlloP alone induced a clear increase in sIPSC frequency, the frequency was not significantly different from control when 1.0 microM AlloP was applied in combination with 10 microM PregS. In addition to the effects on sIPSC parameters, PregS reduced the baseline current evoked by 1.0 microM AlloP in the absence of GABA application or synaptic activity. PregS by itself did not significantly affect the baseline current. The main effects of AlloP and PregS on the sIPSC time course were mimicked by a simplified model with AlloP assumed to reduce the rate of GABA unbinding from the receptor and PregS assumed to increase the rate of desensitization.

  • 48. Halbreich, Uriel
    et al.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
    Eriksson, Elias
    O'brien, Shawn
    Calil, Helena
    Ceskova, Eva
    Dennerstein, Lorraine
    Douki, Saida
    Freeman, Ellen
    Genazzani, Andrea
    Heuser, Isabella
    Kadri, Nadia
    Rapkin, Andrea
    Steiner, Meir
    Wittchen, Hans-Ulrich
    Yonkers, Kimberly
    Clinical diagnostic criteria for premenstrual syndrome and guidelines for their quantification for research studies.2007In: Gynecol Endocrinol, ISSN 0951-3590, Vol. 23, no 3, p. 123-30Article in journal (Refereed)
  • 49. Halbreich, Uriel
    et al.
    O'Brien, P M Shaughn
    Eriksson, Elias
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Clinical Sciences, Obstetrics and Gynaecology.
    Yonkers, Kimberly A
    Freeman, Ellen W
    Are there differential symptom profiles that improve in response to different pharmacological treatments of premenstrual syndrome/premenstrual dysphoric disorder?2006In: CNS Drugs, ISSN 1172-7047, Vol. 20, no 7, p. 523-47Article in journal (Refereed)
  • 50.
    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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