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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.
    Andréen, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sharuh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    van Wingen, Guido
    F.C. Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, The Netherlands.
    Fernández, Guillen
    F.C. Donders Centre for Cognitive Neuroimaging, Radboud University Nijmegen, The Netherlands.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators2009In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 34, no 8, p. 1121-1132Article in journal (Refereed)
    Abstract [en]

    Certain women experience negative mood symptoms as a result of progesterone during the luteal phase of the menstrual cycle, progestagens in hormonal contraceptives, or the addition of progesterone or progestagens in sequential hormone therapy (HT). This phenomenon is believed to be mediated via the action of the progesterone metabolites on the GABA(A) system, which is the major inhibitory system in the mammalian CNS. The positive modulators of the GABA(A) receptor include allopregnanolone and pregnanolone, both neuroactive metabolites of progesterone, as well as benzodiazepines, barbiturates, and alcohol. Studies on the effect of GABA(A) receptor modulators have shown contradictory results; although human and animal studies have revealed beneficial properties such as anaesthesia, sedation, anticonvulsant effects, and anxiolytic effects, recent reports have also indicated adverse effects such as anxiety, irritability, and aggression. It has actually been suggested that several GABA(A) receptor modulators, including allopregnanolone, have biphasic effects, in that low concentrations increase an adverse, anxiogenic effect whereas higher concentrations decrease this effect and show beneficial, calming properties. The allopregnanolone increase during the luteal phase in fertile women, as well as during the addition of progesterone in HT, has been shown to induce adverse mood in women. The severity of these mood symptoms is related to the allopregnanolone serum concentrations in a manner similar to an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. It has also been shown that progesterone/allopregnanolone treatment in women increases the activity in the amygdala (as measured with functional magnetic resonance imaging) in a similar way to the changes seen during anxiety reactions. However, it is evident that only certain women experience adverse mood during progesterone or GABA(A) receptor modulator treatments. Women with premenstrual dysphoric disorder (PMDD) have severe luteal phase related symptoms; in this phase, they show changes in GABA(A) receptor sensitivity and GABA concentrations that are related to the severity of the condition. These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA(A) receptor. CONCLUSION: Progesterone and progestagens induce negative mood, most probably via their GABA(A) receptor active metabolites. In postmenopausal women treated with progesterone and animals treated with allopregnanolone, there is a bimodal association between serum allopregnanolone concentration and adverse mood, resembling an inverted U-shaped curve. In humans, the maximal effective concentration of allopregnanolone for producing negative mood is within the range of physiological luteal phase serum concentrations.

  • 3.
    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)
  • 4.
    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.

  • 5.
    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.

  • 6. Danielsson, C.
    et al.
    Dahmoun, M.
    Bolin, M.
    Agrell, J.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Sundsvalls Cty Hosp, Dept Obstet & Gynaecol, Sundsvall, Sweden.
    Management and outcomes of preterm premature rupture of the membranes2018In: CLINICAL AND EXPERIMENTAL OBSTETRICS & GYNECOLOGY, ISSN 0390-6663, Vol. 45, no 3, p. 419-424Article in journal (Refereed)
    Abstract [en]

    Purpose of investigation: To compare the maternal and neonatal outcomes of preterm premature rupture of the membranes (PPROM) between two management strategies. Materials and Methods: This retrospective cohort study involved 153 pregnant women who presented with PPROM at a gestational age of 28+0 to 36+6 weeks to evaluate the effects of expectant management (EM; labor > 36 hours) and active management (AM; labor < 36 hours) on maternal and neonatal outcomes. The EM and AM groups were also compared independently of gestational age and after being divided into two subgroups: early PPROM (gestational age 28+0 to 33+6 weeks) and late PPROM (34+0 to 36+6 weeks). Results: There were no differences between the AM and EM groups in the rates of maternal infection or placental abruption, or in neonatal outcomes, including low Apgar scores, respiratory distress syndrome, or the need for continuous positive airway pressure (CPAP). In the early PPROM subgroup, arterial umbilical blood base excess levels were more negative in the AM group (p = 0.007). In the late PPROM subgroup, the change in systolic blood pressure between admission to the maternity care center and membrane rupture was greater in the AM group (p = 0.049). Conclusions: There were no clinically significant differences in the maternal and neonatal outcomes of PPROM between AM and EM.

  • 7.
    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.

  • 8.
    Hedström, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Sundsvalls sjukhus, Obstetrik och gynekologi.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Does chronic endogenous exposure to neuroactive steroids change receptor sensitivity to allopregnanolone in humans?Manuscript (preprint) (Other academic)
  • 9.
    Hedström, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Gideonsson, Ida
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA A receptor sensitivity to allopregnanolone2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 5, p. 643-650Article in journal (Refereed)
    Abstract [en]

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

  • 10.
    Holmberg, Ellinor
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Sjöstedt, J.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Malinina, E.
    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.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ragagnin, Gianna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Lundqvist, Anette
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Löfgren, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Jaukkuri, L.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Bixo, Marie
    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.
    Allopregnanolone involvement in feeding regulation, overeating and obesity2018In: Frontiers in neuroendocrinology (Print), ISSN 0091-3022, E-ISSN 1095-6808, Vol. 48, p. 70-77Article, review/survey (Refereed)
    Abstract [en]

    Obesity is strongly associated with ill health, primarily caused by consumption of excessive calories, and promoted (inter alia) by gamma-amino-butyric-acid (GABA) stimulating food intake by activating GABA(A) receptors (primarily with alpha 3 and alpha 2 subunits) in the hypothalamic arcuate nucleus and paraventricular nucleus. Allopregnanolone is a potent positive GABAA receptor modulating steroid (GAMS). As reviewed here, elevated allopregnanolone levels are associated with increases in food intake, preferences for energy-rich food, and obesity in humans and other mammals. In women with polycystic ovarian disease, high serum allopregnanolone concentrations are linked to uncontrolled eating, and perturbed sensitivity to allopregnanolone. Increases in weight during pregnancy also correlate with increases in allopregnanolone levels. Moreover, Prader-Willis syndrome is associated with massive overeating, absence of a GABA(A) receptor (with compensatory > 12-, > 5- and > 1.5-fold increases in alpha 4, gamma 2, and alpha 1, alpha 3 subunits), and increases in the alpha 4, beta x, delta receptor subtype, which is highly sensitive to allopregnanolone. GABA and positive GABA-A receptor modulating steroids like allopregnanolone stimulates food intake and weight gain.

  • 11.
    Klevedal, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Fetal-maternal outcomes and complications in pregnant women with polycystic ovary syndrome2017In: Minerva Ginecologica, ISSN 0026-4784, E-ISSN 1827-1650, Vol. 69, no 2, p. 141-149Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Earlier studies have shown that polycystic ovary syndrome (PCOS) is associated with cardiovascular disease as well as pregnancy complications. We examined whether women with PCOS have an increased risk of complications in pregnancy compared with healthy women, and if there are any correlations between complications and clinical/demographic variables before and/or in early pregnancy.

    METHODS: This retrospective cohort study comprised 37 women with PCOS and 126 healthy women whose birth was recorded at Sundsvall County Hospital, Sweden, from 2009 to 2014. Medical records were searched to identify pregnancy complications, maternal outcomes, and neonatal outcomes.

    RESULTS: Compared with healthy women, the women with PCOS were more likely to have a history of miscarriage (42.9% vs. 19.8% P=0.005) and undergo caesarean section (41.2% vs. 21.4%, P=0.019). They were also at increased risk of developing a complication (odds ratio 2.38, 95% CI: 1.05-5.38) or having multiple concurrent complications (odds ratio 8.27, 95% CI: 1.45-47.3). The rates of premature birth, birth weight and Apgar score at 5 min were similar between the two groups. The preconception serum testosterone concentration was positively correlated with the complication rate and negatively correlated with gestational age.

    CONCLUSIONS: We found that women with PCOS are at greater risk of complications during pregnancy than healthy women, consistent with the results of earlier studies. High testosterone concentrations could be an aggravating factor in the risk of complications. Therefore, women with PCOS may require more careful monitoring during pregnancy than healthy women.

  • 12.
    Löfgren, Magnus
    et al.
    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.
    Meyerson, Bengt
    Department of Neuroscience, Division of Pharmacology, P.O. Box 593, BMC, SE-751 24 Uppsala, Sweden.
    Turkmen, Sahruh
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Withdrawal effects from progesterone and estradiol relate to individual risk-taking and explorative behavior in female rats2009In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 96, no 1, p. 91-97Article in journal (Refereed)
    Abstract [en]

    Withdrawal from progesterone and estradiol has been used as an animal model of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). In the clinical population individual sensitivity to sex steroid hormones, personality and heredity influence PMS/PMDD. Understanding the phenotypic risk factors of PMS/PMDD and drug development requires an animal model which incorporates individual steroid sensitivity. The main objective of this study was to investigate whether the individual trait of risk-taking and exploration influence the severity of PEWD in female rats. Thirty-two female Wistar rats in their diestrus phase were tested in the open field (OF) and divided into high responders (HR) and low responders (LR). Injections were given i.p. twice daily for 6 days, either 5 mg/kg progesterone combined with 10 microg/kg 17beta-estradiol, or vehicle (sesame oil). After a 24-hour withdrawal the animals were tested in the elevated plus maze (EPM). Blood samples for CORT analysis were collected after both behavioral tests. The HR rats withdrawn from progesterone and estradiol, spent less time on the EPM open arms and had lower CORT levels than the HR controls. The LR group showed no differences in EPM behavior and CORT levels during PEWD. The controls showed a stable trait of risk-taking and exploration, indicated by behavioral and CORT level correlations between the OF and EPM tests. These findings show that female rats with the trait of risk-taking and explorative behavior (HR) are more affected by PEWD.

  • 13. Tawhid Söderholm, Nora
    et al.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Department of Obstetrics and Gynecology, Örnsköldsvik Hospital, Örnsköldsvik, Sweden.
    Impact of Epidural Analgesia in Labour onNeonatal and Maternal Outcomes2018In: Open Journal of Obstetrics and Gynecology, ISSN 2160-8792, E-ISSN 2160-8806, Vol. 8, p. 767-779Article in journal (Refereed)
    Abstract [en]

    AimTo evaluate the effect of epidural analgesia during labour on neonatal-maternal outcomes. 

    Methods: A retrospective cohort study of nulliparous parturients who gave birth in Vasternorrland County, Sweden, over a 2-year period between 2015 and 2016. Neonatal outcomes (Apgar score at 5 min and umbilical cord arterial blood gases), maternal outcomes (perineal injury, total bleeding volume and maternal satisfaction with birth) and labour parameters (mode of delivery and the durations of labour and postpartum hospital stay) were evaluated. 

    Results: The study cohort consisted of 1449 women with singleton pregnancies. Patients were divided into two groups according to whether during labour they were administered epidural analgesia using bupivacaine and sufentanil (EDA group, n = 615) or not (non-EDA group, n = 834). The rate of assisted vaginal delivery was significantly higher in the EDA group than in the non-EDA group (15.6% and 11.3%, respectively, p < 0.05), whereas the rates of caesarean section were similar. The duration of the active phase of labour was significantly longer in the EDA group than in the non-EDA group (489 ± 217 min versus 371 ± 210 min, respectively, p < 0.001). The Apgar score at 5 min and umbilical cord blood pH were lower and the base deficit greater in the EDA group (p < 0.001, p < 0.001 and p < 0.01, respectively). Bleeding volume was similar between the groups after adjusting for gestational age. Women in the EDA group were more satisfied with their labour experience, as measured by the visual analogue scale (p < 0.05). 

    Conclusion: The results of this study suggest that EDA affects delivery and neonatal-maternal outcomes negatively, but increases the mother’s satisfaction with labour.

  • 14.
    Turkmen (Ahangari), Sahruh (S)
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Cepni, I
    Ocal P,
    Idil, MH
    Aksu, MF
    Evaluation of different controlled ovarian hyperstimulation (COH) protocols in polycystic ovarian syndrome with assisted reproductive technologies1996In: Cerrahpasa J Med, ISSN 1300-5227, Vol. 27, p. 159-66Article in journal (Refereed)
  • 15.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Maternal and neonatal outcomes in vacuum-assisted delivery with the Kiwi OmniCup and Malmstrom metal cup2015In: Journal of obstetrics and gynaecology research, ISSN 1341-8076, E-ISSN 1447-0756, Vol. 41, no 2, p. 207-213Article in journal (Refereed)
    Abstract [en]

    Aim

    To evaluate the effects of different types of vacuum cups on maternal and neonatal outcomes following assisted vaginal delivery.

    Methods

    A retrospective cohort study was undertaken of all vacuum-assisted deliveries performed over a period of 2years. Patients were divided into two groups according to whether a Kiwi OmniCup (n=230) or Malmstrom metal cup (n=98) was used. Maternal outcomes included maternal genital tract injury and total blood loss. Neonatal outcomes included Apgar score, umbilical cord blood gases, neonatal scalp injury and time spent in the neonatal unit.

    Results

    Maternal or neonatal outcomes and failure rates did not differ between the two groups, however, the duration of the procedure and the fundal pressure maneuver was more frequent in the Malmstrom group.

    Conclusion

    The results of this study suggest that the Kiwi OmniCup and Malmstrom metal cup vacuum extractors are safe and functionally effective for vacuum-assisted delivery.

  • 16.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Tolerance and antagonism to allopregnanolone effects in the rat CNS2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many studies have suggested a relationship between sex steroids and negative mental and mood changes in women. Allopregnanolone, a potent endogenous ligand of the GABA-A receptor and a metabolite of progesterone, is one of the most accused neuroactive steroids. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. In women, there are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone probably develops.

    We have evaluated the 3β-hydroxy pregnane steroid UC1011 as a functional antagonist to allopregnanolone-induced negative effects in rats. In vivo, we used the Morris Water Maze (MWM) test of learning and, in vitro, we studied chloride ion uptake into cortical and hippocampal membrane preparations. The steroid UC1011 reduces the allopregnanolone-induced learning impairment in the MWM and the increase in chloride ion uptake induced by allopregnanolone. To detect whether chronic tolerance develops to an allopregnanolone-induced condition, male rats were pretreated with allopregnanolone injections for three or seven days. These rats were then tested in the Morris Water Maze for five days and compared with relevant controls. Rats with seven days’ allopregnanolone pretreatment experienced improved performance compared with the acutely allopregnanolone-exposed group, reflecting chronic tolerance development. To study the GABA-A receptor changes in acute allopregnanolone tolerance, we used the silent second (SS) anaesthesia threshold method. At acute tolerance, 90 minutes of anaesthesia, the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the thalamus ventral-posteriomedial (VPM) nucleus were reduced. There was also a significant negative correlation between the increase in the allopregnanolone dose needed to maintain anaesthesia and the α4 mRNA in the VPM nucleus. We also investigated whether allopregnanolone tolerance was still present one or two days after the end of the anaesthesia-induced acute tolerance. Tolerance persisted to one day, but not two days, after the treatment and the α4 subunit mRNA expression in the VPM nucleus was negatively related to the allopregnanolone doses needed after one day.

    In conclusion, the current thesis shows that the substance UC1011 can reduce the allopregnanolone-induced negative effects in the water maze test. Chronic allopregnanolone tolerance can develop to the effects of allopregnanolone. Allopregnanolone tolerance persists one day after the induction of acute allopregnanolone tolerance. The GABA-A receptor α4 subunit in the thalamus might be involved in the development and persistence of acute tolerance to allopregnanolone.

  • 17.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ahangari, Alebtekin
    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.
    Roux-en-Y Gastric Bypass Surgery in Patients with Polycystic Ovary Syndrome and Metabolic Syndrome2016In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 26, no 1, p. 111-118Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We aimed to evaluate the impact of Roux-en-Y gastric bypass (RYGB) surgery on metabolic syndrome-related variables in obese women with polycystic ovarian syndrome (PCOS).

    METHODS: Thirteen obese women with PCOS (Rotterdam criteria) who met the International Diabetes Federation criteria for metabolic syndrome and who qualified for RYGB were enrolled. Clinical examinations included ovarian ultrasonography and measurement of waist, hip, body mass index and blood pressure. Venous blood samples were taken at the visit before surgery to measure triglyceride, high-density lipoprotein, low-density lipoprotein, fasting glucose, glycated haemoglobin (HbA1c), serum progesterone, allopregnanolone, total testosterone and sex hormone-binding globulin (SHBG) levels. Six months after surgery, patients underwent the same examinations and provided blood samples to analyse the same variables.

    RESULTS: At 6 months after surgery, the metabolic syndrome-related variables improved in all patients, except in six patients with anovulatory menstrual cycles who still satisfied the criteria for metabolic syndrome. The metabolic variables normalised and serum progesterone and allopregnanolone levels increased in seven patients with ovulatory cycles. Testosterone and SHBG normalised in all patients at 6 months after surgery. Serum HDL and diastolic blood pressure did not change after surgery. Correlations were found among testosterone, progesterone, allopregnanolone, lipoproteins, triglyceride, fasting glucose and HbA1c levels, which was interpreted as progesterone and its metabolite allopregnanolone may contribute to metabolic abnormalities.

    CONCLUSIONS: In PCOS patients, normalisation of metabolic dysfunction may be incomplete by 6 months after RYGB surgery, and the start of ovulatory menstrual cycles may indicate normalisation of metabolic dysfunction.

  • 18.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Andreen, Lotta
    Cengiz, Yücel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Effects of Roux-en-Y gastric bypass surgery on eating behaviour and allopregnanolone levels in obese women with polycystic ovary syndrome2015In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 31, no 4, p. 301-305Article in journal (Refereed)
    Abstract [en]

    Polycystic ovary syndrome (PCOS) is associated with abnormal eating habits. We examined whether surgical treatment affected allopregnanolone levels and eating behaviour in nine women with PCOS who qualified for Rou-en-Y gastric bypass surgery. Blood samples were obtained to measure sex-hormone-binding globulin, total testosterone, progesterone, and allopregnanolone, and eating behaviour was evaluated using the Three-Factor Eating Questionnaire before surgery and at 6 and 12 months after surgery. Body mass index and total testosterone levels decreased, and progesterone and sex-hormone-binding globulin levels increased after bariatric surgery compared with pre-surgical values. In patients with anovulatory menstrual cycles, both the serum allopregnanolone level and the allopregnanolone/progesterone ratio were unchanged after surgery. The patients had high uncontrolled and emotional eating scores, and low cognitive restraint scores before surgery, and these scores had improved significantly at 6 and 12 months after surgery. The presurgical allopregnanolone levels were significantly correlated with uncontrolled eating. In conclusion, these results suggest that allopregnanolone appear to be part of the mechanism underlying the abnormal eating behaviour of obese PCOS patients by causing the loss of control over food intake. Roux-en-Y gastric bypass surgery can improve eating behaviour and clinical symptoms, and may facilitate weight loss in obese women with PCOS.

  • 19.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Backstrom, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Idil, M
    Reduction of dehydroepiandrosterone sulfate synthesis in women with polycystic ovary syndrome by human menopausal gonadotropin but not purified urinary follicle stimulating hormone: a comparative pilot study.2004In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 19, no 2Article in journal (Refereed)
    Abstract [en]

    We aimed to compare the effects of two different gonadotropins on steroid production in patients with polycystic ovary syndrome (PCOS). The study group comprised 20 infertile patients diagnosed with PCOS who were accepted into in vitro fertilization-embryo transfer and gamete intra-Fallopian transfer programs. Ten patients were consecutively allocated to a purified urinary follicle stimulating hormone (FSH) administration group while the other ten received human menopausal gonadotropin (hMG). All patients were pretreated with a gonadotropin releasing hormone-agonist. The patients were followed by daily vaginal ultrasonography until at least two follicles reached a diameter of 17 mm or an estradiol value of at least 100 pg/ml per follicle. To induce ovulation, human chorionic gonadotropin was given. On the 3rd day of menstruation, serum estradiol, luteinizing hormone (LH), FSH, total testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), insulin-like growth factor-I and insulin were measured. These same parameters were measured again on the day of follicle aspiration in both serum and follicular fluid. In both groups, the serum levels of estradiol and androstenedione were raised significantly, and on aspiration day the serum level of DHEAS was significantly raised in the FSH group but not in the hMG group. Our findings suggest that in PCOS patients exogenous hMG induces a different steroid synthesis pattern compared to pure FSH, hypothetically by reduction of the delta-5 steroid synthesis pathway in the adrenals and/or in the ovary.

  • 20.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hedström, Helena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Gideonsson, Ida
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wang, Mingde
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    The author's reply: Blood allopregnanolone levels in women with polycystic ovary syndrome2016In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 85, no 1, p. 152-154Article in journal (Refereed)
  • 21.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sundsvall, Sweden.
    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.
    Andréen, Lotta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sundsvall, Sweden.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Tolerance to allopregnanolone with focus on the GABA-A receptor2011In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 162, no 2, p. 311-327Article in journal (Refereed)
    Abstract [en]

    Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid -A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial (VPM) nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors.

  • 22.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Department of Obstetrics and Gynecology, Sundsvall County Hospital, Sundsvall 85186, Sweden.
    Johansson, Simona
    Dahmoun, Marju
    Foetal Macrosomia and Foetal-Maternal Outcomes at Birth2018In: Journal of Pregnancy, ISSN 2090-2727, E-ISSN 2090-2735, article id 4790136Article in journal (Refereed)
    Abstract [en]

    To investigate how macrosomia affects foetal-maternal birth outcomes, we conducted a retrospective cohort study of singleton pregnant women who gave birth at gestational age >= 37+0 weeks. The patients were divided into three groups according to birth weight: "macrosomia" group, >= 4500 g, n=285; "upper-normal" group, 3500-4499 g, n=593; and "normal" group, 2500-3499 g, n=495. Foetal-maternal and delivery outcomes were compared among the three groups after adjustment for confounders. Caesarean section was more frequent in the macrosomia group than in upper-normal and normal groups. The duration of labour (p < 0.05) and postpartum care at the hospital (p < 0.001) were the highest in the macrosomia group. Increased birth weight was associated with higher risks of shoulder dystocia (p < 0.001), increased bleeding volume (p < 0.001), and perineal tear (p < 0.05). The Apgar score at 5 minutes (p < 0.05), arterial cord pH (p < 0.001), and partial pressure of O2 (p < 0.05) were lower, while the arterial cord partial pressure of CO2 was higher (p < 0.001), in the macrosomia group. Macrosomia has potentially serious impacts for neonate and mother as a result of a complicated and occasionally traumatic delivery.

  • 23.
    Turkmen, Sahruh
    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.
    Birzniece, Vita
    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.
    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.
    3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) antagonism of the GABA potentiation and the learning impairment induced in rats by allopregnanolone.2004In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 20, no 6, p. 1604-1612Article in journal (Refereed)
    Abstract [en]

    Allopregnanolone is a progesterone metabolite and GABA-A receptor modulator with benzodiazepine like effects, including decreased learning and memory. In vitro 3beta-hydroxypregnane steroids antagonize allopregnanolone-induced effects, but no antagonism has been shown in vivo. Our purpose was to evaluate 3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) as a blocker of allopregnanolone-induced effects in vivo and in vitro in rats. We tested adult male Wistar rats in the Morris water maze 8 min after daily injections (i.v.) of allopregnanolone 2 mg/kg (n = 21); allopregnanolone : UC1011 2 : 6 (n = 7), 2 : 8 (n = 7), 2 : 20 (n = 14) mg/kg; UC1011 20 mg/kg (n = 14); or vehicle (10% 2-hydroxypropyl-beta-cyclodextrin, n = 4). Studies of chloride ion uptake into cortical and hippocampal membrane preparations were performed. The latency to find the hidden platform was still high in the allopregnanolone-injected group on day 6. Day 3-6 rats injected with allopregnanolone and UC1011 (2 : 20 mg/kg) had lower latency (P < 0.05), compared to the allopregnanolone-injected group. The group that only received UC1011 learned the location of the platform as fast as the controls. There was no significant difference in swim speed between groups. The time spent swimming close to the pool wall was in the allopregnanolone : UC1011 group (2 : 20 mg/kg) significantly decreased (P < 0.05, day 3-6), compared to the allopregnanolone-injected group. The increased chloride ion uptake induced by increasing dosage of allopregnanolone in the presence of 10 micro m GABA was significantly decreased with UC1011 (P < 0.01), in both cortical and hippocampal homogenates. In conclusion, UC1011 can via antagonism at the GABA-A receptor reduce the negative allopregnanolone effect on learning in the water maze.

  • 24.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Tjernström, Maja
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Dahmoun, Marju
    Bolin, Marie
    Post-partum duration of satisfaction with childbirth2018In: Journal of obstetrics and gynaecology research, ISSN 1341-8076, E-ISSN 1447-0756, Vol. 44, no 12, p. 2166-2173Article in journal (Refereed)
    Abstract [en]

    AIM: Satisfaction with childbirth has become increasingly important among healthcare providers. We evaluated whether satisfaction levels change with time (up to 3 months after delivery).

    METHODS: A prospective study of nulliparous women was designed to evaluate their levels of satisfaction with childbirth and care during birth in the maternity unit of a county hospital in Sundsvall, Sweden. Patient satisfaction with birth and health care was measured twice, during the first week after birth and 3 months later, with the Childbirth Experience Questionnaire (CEQ). Maternal and labor information were collected with a form filled in by the patients and completed with information from the patients' records.

    RESULTS: A total of 78 primiparous women participated in the study and answered the questionnaire in the first week after labor, and 63 of them completed the study by answering the same questionnaire 3 months after delivery. The total CEQ score did not change after 3 months, but the scores for the subscales 'professional support' and 'participation' decreased 3 months after labor (P = 0.008 and P = 0.001, respectively). A visual analogue scale predicted the total CEQ scores at both 1 week (P < 0.001) and 3 months (P = 0.003).

    CONCLUSION: Our results indicate that satisfaction with labor and birth among primiparous women was unchanged 3 months after labor.

  • 25.
    Turkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlstrom, Goran
    Backstrom, Torbjorn
    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.
    Persistence of tolerance to the anaesthetic effect of allopregnanolone in male ratsManuscript (Other academic)
  • 26.
    Türkmen, Sahruh
    et al.
    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.
    Birzniece, Vita
    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.
    Tolerance development to Morris water maze test impairments induced by acute allopregnanolone2006In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 139, no 2, p. 651-659Article in journal (Refereed)
    Abstract [en]

    The progesterone metabolite allopregnanolone, like benzodiazepines, reduces learning and impairs memory in rats. Both substances act as GABA agonists at the GABA-A receptor and impair the performance in the Morris water maze test. Women are during the menstrual cycle, pregnancy, and during hormone replacement therapy exposed to allopregnanolone or allopregnanolone-like substances for extended periods. Long-term benzodiazepine treatment can cause tolerance against benzodiazepine-induced learning impairments. In this study we evaluated whether a corresponding allopregnanolone tolerance develops in rats. Adult male Wistar rats were pretreated for 3 days with i.v. allopregnanolone injections (2 mg/kg) one or two times a day, or for 7 days with allopregnanolone injections 20 mg/kg intraperitoneally, twice a day. Thereafter the rats were tested in the Morris water maze for 5 days and compared with relevant controls. Rats pretreated with allopregnanolone twice a day had decreased escape latency, path length and thigmotaxis compared with the acute allopregnanolone group that was pretreated with vehicle. Pretreatment for 7 days resulted in learning of the platform position. However, the memory of the platform position was in these tolerant rats not as strong as in controls only given vehicle. Allopregnanolone treatment was therefore seen to induce a partial tolerance against acute allopregnanolone effects in the Morris water maze.

  • 27.
    Türkmen, Sahruh
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Persistence of tolerance to the anaesthetic effect of allopregnanolone in male rats.2008In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 592, no 1-3, p. 73-80Article in journal (Refereed)
    Abstract [en]

    Both acute and chronic tolerance can develop to allopregnanolone-a gamma-aminobutyric acid (GABA)-modulatory progesterone metabolite. Here we investigated if acute tolerance to allopregnanolone persisted for 1 or 2 days after the induction and thus could be the initial part of chronic tolerance. Male rats were anaesthetised with allopregnanolone (i.v) to the deep anaesthesia level of the silent second (SS), which is an EEG burst suppression of 1 s or more. They were divided into four groups: SS1-anaesthesia to the first silent second; LAn (long anaesthesia)-90 min anaesthesia at the SS level; SS2;D1-90 min anaesthesia and SS induction 1 day later; SS2;D2-90 min anaesthesia and SS induction 2 days later. Allopregnanolone concentrations in tissue and serum were analysed. Levels of the GABAA receptor alpha2, alpha4, gamma2(S+L) and delta subunits mRNAs were analysed by in situ hybridisation. Acute tolerance was induced during the 90 min anaesthesia. Tolerance persisted for 1 day, since the dose of allopregnanolone needed to induce a new SS anaesthesia was increased after 1 day. The level of alpha4 subunit mRNA expression in the ventral posteriomedial nucleus of thalamus was negatively related to the tolerance parameters, the SS dose of allopregnanolone and DeltaSS (SS dose difference between days). Allopregnanolone threshold anaesthesia lasting 90 min induces acute tolerance that persisted for at least 1 day, which could be used as the start of a chronic tolerance. The alpha4 subunit may be involved in allopregnanolone caused effects in the brain.

  • 28.
    Öfverman, Charlotte
    et al.
    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.
    Birzniece, Vita
    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.
    Hill, Martin
    Institute of Endocrinology, Nároní trída 8, CZ 116 94, Prague, Czech Republic.
    Lundgren, Per
    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.
    The progesterone metabolite isoallopregnanolone is a subunit-selective antagonist of the GABA-A receptorManuscript (preprint) (Other academic)
    Abstract [en]

     Allopregnanolone is a progesterone metabolite that can negatively affect learning and induce anaesthesia in rats. It also impairs episodic memory in women. Allopregnanolone levels are elevated during the luteal phase of the menstrual cycle, during pregnancy, and during stress. Allopregnanolone is a strong positive modulator of the GABAA receptor. The subunit composition of the GABAA receptor is of importance for effects of modulators, and GABAA receptors including the α5-subunit are of significance for learning, while receptors with other subunits are involved in e.g. anesthesia. Isoallopregnanolone, a natural 3β-epimer of allopregnanolone, has been shown to antagonize allopregnanolone-induced anesthesia in rats.

    We tried to block the allopregnanolone-induced impairment of learning in rats in the Morris water maze test, using isoallopregnanolone (4–32 mg/kg). We also determined steroid concentrations in blood and brain tissue, and with whole-cell patch clamp we studied the effects of isoallopregnanolone and tetrahydrodeoxycorticosterone (a neurosteroid similar to allopregnanolone) on HEK-293 cells expressing the human α5β2γ2L GABAA receptor.

    Isoallopregnanolone did not block the negative effects of allopregnanolone (2 mg/kg) in the Morris water maze test. Our presumed antagonist actually had an agonistic effect on the tetrahydrodeoxycorticosterone-mediated potentiation of the GABA effect on the α5β2γ2L GABAA receptor. The baseline shift induced by tetrahydrodeoxycorticosterone alone was not reversed by isoallopregnanolone. A bidirectional epimerisation between allopregnanolone and isoallopregnanolone was also identified in the rat.

    The lack of antagonistic effect at the α5β2γ2L GABAA receptor together with the epimerisation of isoallopregnanolone to allopregnanolone would probably explain the lack of effect of our proposed antagonist on the allopregnanolone-induced impairment of learning 

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