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  • 1.
    Andréen, Lotta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Turkmen, Sharuh
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    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 universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators2009Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 34, nr 8, s. 1121-1132Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    Andréen, Lotta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Sundström-Poromaa, Inger
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Andersson, Agneta
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone.2005Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, nr 2, s. 212-224Artikel i tidskrift (Refereegranskat)
  • 3.
    Bendix, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Wihlbäck, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Ahokas, Antti
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Allopregnanolone and progesterone in estradiol treated severe postpartum affective disorder2019Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 107, s. 68-68Artikel i tidskrift (Övrigt vetenskapligt)
  • 4.
    Bendix, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Uvnas-Moberg, Kerstin
    Petersson, Maria
    Asberg, Marie
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap. Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Higher insulin and lower glucagon levels in plasma and cerebrospinal fluid in suicide attempters compared to healthy controls2016Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 71, s. 26-26Artikel i tidskrift (Övrigt vetenskapligt)
  • 5.
    Bendix, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Uvnas-Moberg, Kerstin
    Petersson, Maria
    Gustavsson, Petter
    Svanborg, Par
    Asberg, Marie
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Plasma oxytocin and personality traits in psychiatric outpatients2015Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 57, s. 102-110Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The oxytocin system is regarded as being of relevance for social interaction. In spite of this, very few studies have investigated the relationship between oxytocin and personality traits in clinical psychiatric populations. We assessed the relationship between personality traits and plasma oxytocin levels in a population of 101 medication-free psychiatric outpatients (men = 37, women = 64). We used the Karolinska Scale of Personality (KSP) and diagnostic and symptomatic testing. Plasma oxytocin levels were analysed with a specific radioimmunoassay at inclusion and after one month for testing of stability. Plasma oxytocin levels were stable over time and did not differ between patients with or without personality disorders, nor were they related to severity of depressive or anxiety symptoms. The KSP factors Impulsiveness and Negative Emotionality were significant independent predictors of plasma oxytocin. A subscale analysis of these personality factors showed significant positive correlations between baseline plasma oxytocin and the KSP subscales monotony avoidance and psychic anxiety. The significant association between the KSP factor Impulsiveness and oxytocin levels observed at baseline was observed also one month later in men. These findings suggest that personality traits such as Impulsiveness and Negative emotionality which are linked to social functioning in several psychiatric disorders seem to be associated with endogenous plasma oxytocin levels. These variations in oxytocin levels might have an impact on social sensitivity or social motivation with possible gender differences.

  • 6.
    Bendix, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Uvnäs-Moberg, Kerstin
    Petersson, Maria
    Kaldo, Viktor
    Åsberg, Marie
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Corrigendum to "Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls" [Psychoneuroendocrinology 81 (2017) 1-7]2018Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 94, artikel-id 168Artikel i tidskrift (Refereegranskat)
  • 7.
    Bendix, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Uvnäs-Moberg, Kerstin
    Petersson, Maria
    Kaldo, Viktor
    Åsberg, Marie
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls2017Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 81, s. 1-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mental disorders and related behaviors such as suicidality and violence have been associated to dysregulation of e g carbohydrate metabolism. We hypothesized that patients after suicide attempt, compared to healthy controls, would have higher insulin and lower glucagon levels in plasma and cerebrospinal fluid and that these changes would be associated to violent behavior. Twenty-eight medication-free patients (10 women, 18 men), hospitalized after suicide attempt, and 19 healthy controls (7 women, 12 men) were recruited with the aim to study risk factors for suicidal behavior. Psychological/psychiatric assessment was performed with SCID I and II or the SCID interview for healthy volunteers respectively, the Karolinska Interpersonal Violence Scale (KIVS) for assessment of lifetime violence expression behavior, the Montgomery-Asberg-Depression-Scale (MADRS) and the Comprehensive Psychological Rating Scale (CPRS) for symptomatic assessment of depression and appetite. Fasting levels of insulin and glucagon were measured in plasma (P) and cerebrospinal fluid (CSF). Suicide attempters had higher insulin- and lower glucagon-levels in plasma- and CSF compared to controls. Except for P-glucagon these associations remained significant after adjusting for age and/or BMI. Patients reported significantly more expressed interpersonal violence compared to healthy volunteers. Expressed violence was significantly positively correlated with P- and CSF-insulin and showed a significant negative correlation with P-glucagon in study participants. These findings confirm and extend prior reports that higher insulin and lower glucagon levels in plasma and cerebrospinal fluid are associated with suicidal behavior pointing towards a potential autonomic dysregulation in the control of insulin and glucagon secretion in suicidal patients. 

  • 8.
    Bengtsson, Sara K. S.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Hedström, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Zingmark, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Jonsson, Bjorn
    Bäckström, Torbjörn
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans2015Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 52, s. 22-31Artikel i tidskrift (Refereegranskat)
    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.

  • 9. Bixo, M
    et al.
    Allard, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Bäckström, T
    Mjörndal, T
    Nyberg, S
    Spigset, O
    Sundström-Poromaa, I
    Binding of [3H]paroxetine to serotonin uptake sites and of [3H]lysergic acid diethylamide to 5-HT2A receptors in platelets from women with premenstrual dysphoric disorder during gonadotropin releasing hormone treatment.2001Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 26, nr 6, s. 551-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Changes in serotonergic parameters have been reported in psychiatric conditions such as depression but also in the premenstrual dysphoric disorder (PMDD). In addition, hormonal effects on serotonergic activity have been established. In the present study, binding of [3H]paroxetine to platelet serotonin uptake sites and binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors were studied in patients with PMDD treated with a low dose of a gonadotropin releasing hormone (GnRH) agonist (buserelin) or placebo and compared to controls. The PMDD patients were relieved of premenstrual symptoms like depression and irritability during buserelin treatment. The number of [3H]paroxetine binding sites (Bmax) were significantly higher in the follicular phase in untreated PMDD patients compared to controls. When treated with buserelin the difference disappeared. No differences in [3H]LSD binding between the three groups were shown. The present study demonstrated altered platelet [3H]paroxetine binding characteristics in women with PMDD compared to controls. Furthermore, [3H]paroxetine binding was affected by PMDD treatment with a low dose of buserelin. The results are consistent with the hypothesis that changes in serotonergic transmission could be a trait in the premenstrual dysphoric disorder.

  • 10.
    Bixo, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Ekberg, Karin
    Poromaa, Inger Sundstrom
    Hirschberg, Angelica Linden
    Jonasson, Aino Fianu
    Andreen, Lotta
    Timby, Erika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Wulff, Marianne
    Ehrenborg, Agneta
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Treatment of premenstrual dysphoric disorder with the GABA(A) receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial2017Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 80, s. 46-55Artikel i tidskrift (Refereegranskat)
    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.

  • 11. Brenner, Philip
    et al.
    Granqvist, Mathias
    Königsson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Al Nimer, Faiez
    Piehl, Fredrik
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Division of Psychiatry, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Depression and fatigue in multiple sclerosis: Relation to exposure to violence and cerebrospinal fluid immunomarkers2018Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 89, s. 53-58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multiple sclerosis (MS) is a neuroinflammatory condition characterized by chronic dysregulation of immune responses leading to repeated episodes of inflammation in the central nervous system. Depression and fatigue are common among MS patients, even in early disease phases, and the disease course can be negatively affected by stressful events. IL-6 and IL-8 have been associated with depression and stressful life events in non-MS patients. The aim of this study was to examine the relationships between depression, fatigue, and exposure to violence, with IL-6 and IL-8 levels in the cerebrospinal fluid (CSF) of MS patients. Levels of IL-6 and -8 were analyzed in the CSF of 47 patients with relapsing-remitting MS. Correlations between IL-6 and IL-8 levels and self-rated depression and fatigue symptoms, as well as clinician-rated history of being exposed to interpersonal violence, were analyzed with correction for age, sex and MS disability status. IL-6 correlated significantly (p < 0.05) with depressive symptoms (adjusted Spearman’s ρ = 0.39), fatigue (ρ = 0.39), and exposure to violence in adult life (ρ = 0.35). Depression correlated with both fatigue and being exposed to violence. Associations were not present among patients exposed to disease modifying drugs. In exploratory analyses, the relationship between exposure to violence and IL-6 was non-significant when controlled for depression. Further research should focus on replication of these results, as well as exploring the impact of stressful life events on immune regulation and the clinical characteristics and prognosis of MS patients.

  • 12.
    Bäckström, Torbjörn
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Savic, Ivanka
    Increased neurosteroid sensitivity - An explanation to symptoms associated with chronic work related stress in women?2013Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, nr 7, s. 1078-1089Artikel i tidskrift (Refereegranskat)
    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.

  • 13. Chatzittofis, Andreas
    et al.
    Arver, Stefan
    Öberg, Katarina
    Hallberg, Jonas
    Nordström, Peter
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    HPA axis dysregulation in men with hypersexual disorder2016Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 63, s. 247-253Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hypersexual disorder integrating pathophysiological aspects such as sexual desire deregulation, sexual addiction, impulsivity and compulsivity was suggested as a diagnosis for the DSM-5. However, little is known about the neurobiology behind this disorder. A dysregulation of the hypothalamic pituitary adrenal (HPA) axis has been shown in psychiatric disorders but has not been investigated in hypersexual disorder. The aim of this study was to investigate the function of the HPA axis in hypersexual disorder. The study includes 67 male patients with hypersexual disorder and 39 healthy male volunteers. Basal morning plasma levels of cortisol and ACTH were assessed and low dose (0.5 mg) dexamethasone suppression test was performed with cortisol and ACTH measured post dexamethasone administration. Non-suppression status was defined with DST-cortisol levels >= 138 nmol/l. The Sexual Compulsive scale (SCS), Hypersexual disorder current assessment scale (HD:CAS), Montgomery-Asberg Depression Scale-self rating (MADRS-S) and Childhood trauma questionnaire (CTQ), were used for assessing hypersexual behavior, depression severity and early life adversity. Patients with hypersexual disorder were significantly more often DST non-suppressors and had significantly higher DST-ACTH levels compared to healthy volunteers. The patients reported significantly more childhood trauma and depression symptoms compared to healthy volunteers. CTQ scores showed a significant negative correlation with DST-ACTH whereas SCS and HD:CAS scores showed a negative correlation with baseline cortisol in patients. The diagnosis of hypersexual disorder was significantly associated DST non-suppression and higher plasma DST-ACTH even when adjusted for childhood trauma. The results suggest HPA axis dysregulation in male patients with hypersexual disorder.

  • 14. Chatzittofis, Andreas
    et al.
    Arver, Stefan
    Öberg, Katarina
    Hallberg, Jonas
    Nordström, Peter
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    HPA axis dysregulation in patients with hypersexual disorder2015Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 61, s. 53-53Artikel i tidskrift (Övrigt vetenskapligt)
  • 15. Dahlman, Anna Sjors
    et al.
    Jonsdottir, Ingibjorg H.
    Hadrévi, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    Burnout patients' metabolic responses to acute stress2019Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 107, s. 24-25Artikel i tidskrift (Övrigt vetenskapligt)
  • 16. Ehlert, Ulrike
    et al.
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Stockholm Cty Council, Dept Clin Neurosci, Ctr Psychiat Res, Stockholm, Sweden; Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden; Karolinska Inst, Stockholm, Sweden.
    Sexual steroids during the course of female life2019Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 107, s. 67-67Artikel i tidskrift (Övrigt vetenskapligt)
  • 17.
    Gustafsson, Per E
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Anckarsäter, Henrik
    Lichtenstein, Paul
    Nelson, Nina
    Gustafsson, Per A
    Does quantity have a quality all its own? Cumulative adversity and up- and down-regulation of circadian salivary cortisol levels in healthy children.2010Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 35, nr 9, s. 1410-1415Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Findings have been divergent regarding the direction of basal cortisol dysregulations resulting from stressor exposure, and seem to differ between young people and adults. Accumulated stress exposure has been suggested to be a risk factor for the development of hypocortisolism. This cross-sectional study aims to examine the impact of cumulative adversity, i.e., the number of adversities, on diurnal salivary cortisol levels, including the cortisol awakening response (CAR), in children without psychiatric disorder. The sample consisted of 130 children (mean age 12.8 years), representing one in each twin pair included in the population-based Child and Adolescent Twin Study in Sweden (CATSS). Information about socioeconomic disadvantage, negative life events and potentially traumatic life events were collected by telephone interview and questionnaires, with parents as informants. Salivary cortisol sampling was performed in the home during two school days: at awakening, +30 min post-awakening, and at bedtime. Results showed that the number of adversities was related to the CAR, diurnal decline and +30 min post-awakening cortisol levels. Children with a moderate amount of cumulative adversity displayed high cortisol measures, while those with a high amount (3 or more) of adversities instead showed levels similar to the non-exposed group, yielding an inverse U-pattern of the association between cortisol and adversity. These results indicate that the accumulation of adversity might be an explanation of patterns of basal cortisol up-regulation in children and that those most severely exposed can exhibit an early stage of down-regulation, an issue which should be further examined in longitudinal studies.

  • 18.
    Gustafsson, Per E
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Janlert, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Theorell, Töres
    Stress Research Institute, Stockholm University, Stockholm, Sweden.
    Hammarström, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Life-course socioeconomic trajectories and diurnal cortisol regulation in adulthood2010Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 35, nr 4, s. 613-623Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although the health risk of socioeconomic disadvantage over the life-course is fairly established, the mechanisms are less studied. One candidate pathway is long-term dysregulation of cortisol. This study assesses whether socioeconomic trajectories from adolescence to adulthood influences the regulation of cortisol in mid-adulthood, and further investigates the importance of adolescence as a critical period and of accumulation of socioeconomic disadvantage. Participants were drawn from a 27-year prospective cohort study (n = 732, 68% of the original cohort). Information on socioeconomic status (SES) was collected at the ages of 16 (based on parental occupation), 21, 30 and 43 (based on own occupation) years, and at 43 years participants collected one-day salivary cortisol samples at awakening, after 15 min, before lunch and at bedtime. We found that the cortisol awakening response (CAR) differed with respect to SES trajectory; those with stable low or early low/upwardly mobile SES tended to display higher CAR than those with early high/downwardly mobile, highly mobile or stable high trajectories. Further analyses revealed that early low SES was related to higher CAR, and in women low SES was related to lower bedtime cortisol, independently of later SES and potential confounders. We found no support for a linear effect of accumulation of socioeconomic disadvantage. In conclusion, our study gives support for an independent effect of low socioeconomic status early in life, on the regulation of cortisol in adulthood.

  • 19.
    Gustafsson, Per E.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Janlert, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Virtanen, Pekka
    Hammarström, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    The association between long-term accumulation of temporary employment, the cortisol awakening response and circadian cortisol levels2012Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 37, nr 6, s. 789-800Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Temporary employment is an increasingly common contract type, which has not been investigated in a psychoneuroendocrinological context despite previous observations of associations between adverse work and employment conditions and hypothalamic-pituitary-adrenal (HPA) axis dysregulations. The present study aims to examine whether the 12-year accumulation of temporary employment is related to circadian cortisol levels, and if any association is independent of current employment conditions. Participants were drawn from the prospective Northern Swedish Cohort (n = 791, 74% of the original cohort). At age 43 years, retrospective reports of employments over the last 12 years and of current social conditions were collected by questionnaire, and one-day salivary cortisol profile was measured (at awakening, +15 min post-awakening, pre-lunch, bedtime). Results indicated a gradually higher magnitude of the cortisol awakening response (CAR) in subjects with no (0 months in temporary employment; mean CAR = 34%), moderate (1-25 months in temporary employment; mean CAR = 41%) and heavy (>25 months in temporary employment; mean CAR = 51%) exposure (p = .020), remaining after adjustment for potential confounders and for current employment conditions (p = .028). The higher CAR was explained by lower awakening rather than higher post-awakening cortisol levels. Cortisol levels at all times of the day except post-awakening displayed tendencies to negative relations to temporary employment; as indicated by a lower Area Under of Curve (regression coefficient = 5.0%, p = .038 after adjustment). This study thus suggests that the long-term exposure to temporary employment might confer HPA dysregulations in the form of increased dynamics of the CAR and circadian suppression. (C) 2011 Elsevier Ltd. All rights reserved.

  • 20. Henningsson, Susanne
    et al.
    Westberg, Lars
    Nilsson, Staffan
    Lundström, Bengt
    Ekselius, Lisa
    Bodlund, Owe
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Lindström, Eva
    Hellstrand, Monika
    Rosmond, Roland
    Eriksson, Elias
    Landén, Mikael
    Sex steroid-related genes and male-to-female transsexualism2005Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, nr 7, s. 657-664Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transsexualism is characterised by Lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and-after aromatase-catalyzed conversion to estradiol-via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ER beta gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy mate controls. Transsexuals differed from controls with respect to the mean Length of the ER repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.

  • 21. Holmer, Helene
    et al.
    Svensson, Johan
    Rylander, Lars
    Johannsson, Gudmundur
    Rosen, Thord
    Bengtsson, Bengt-Ake
    Thoren, Marja
    Hoybye, Charlotte
    Degerblad, Marie
    Bramnert, Margareta
    Hägg, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Engstrom, Britt Eden
    Ekman, Bertil
    Erfurth, Eva-Marie
    Psychosocial health and levels of employment in 851 hypopituitary Swedish patients on long-term GH therapy2013Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, nr 6, s. 842-852Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: The psychosocial health and working capacity in hypopituitary patients receiving long-term growth hormone (GH) therapy are unknown. Objective: Psychosocial health and levels of employment were compared between GH deficient (GHD) patients on long-term replacement and the general population. Design and participants: In a Swedish nationwide study, 851 GHD patients [101 childhood onset (CO) and 750 adult onset (AO)] and 2622 population controls answered a questionnaire regarding current living, employment and educational level, alcohol consumption and smoking habits. The median time on GH therapy for both men and women with CO GHD was 9 years and for AO GHD 6 years, respectively. Results: As compared to the controls, the GHD patients were less often working full time, more often on sick leave/disability pension, and to a larger extent alcohol abstainers and never smokers (all; P < 0.05). Predominantly CO GHD women and men, but to some extent also AO GHD women and men, lived less frequently with a partner and more often with their parents. Particularly AO GHD craniopharyngioma women used more antidepressants, while AO GHD men with a craniopharyngioma used more analgesics. Conclusions: A working capacity to the level of the general population was not achieved among hypopituitary patients, although receiving long-term GH therapy. Patients were less likely to use alcohol and tobacco. The CO GHD population lived a less independent life. (C) 2012 Elsevier Ltd. All rights reserved.

  • 22.
    Jokinen, Jussi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    Bostrom, Adrian E.
    Chatzittofis, Andreas
    Ciuculete, Diana M.
    Oberg, Katarina Gorts
    Flanagan, John N.
    Arver, Stefan
    Schioth, Helgi B.
    Methylation of HPA axis related genes in men with hypersexual disorder2017Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 80, s. 67-73Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hypersexual Disorder (HD) defined as non-paraphilic sexual desire disorder with components of compulsivity, impulsivity and behavioral addiction, and proposed as a diagnosis in the DSM 5, shares some overlapping features with substance use disorder including common neurotransmitter systems and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function. In this study, comprising 67 HD male patients and 39 male healthy volunteers, we aimed to identify HPA-axis coupled CpG-sites, in which modifications of the epigenetic profile are associated with hypersexuality. The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip, measuring the methylation state of over 850 K CpG sites. Prior to analysis, the global DNA methylation pattern was pre-processed according to standard protocols and adjusted for white blood cell type heterogeneity. We included CpG sites located within 2000 bp of the transcriptional start site of the following HPA-axis coupled genes: Corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor I (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FKBP5 and the glucocorticoid receptor (NR3C1). We performed multiple linear regression models of methylation M-values to a categorical variable of hypersexuality, adjusting for depression, dexamethasone non-suppression status, Childhood Trauma Questionnaire total score and plasma levels of TNF-alpha and IL-6. Of 76 tested individual CpG sites, four were nominally significant (p<0.05), associated with the genes CRH, CRHR2 and NR3C1. Cg23409074-located 48 bp upstream of the transcription start site of the CRH gene - was significantly hypomethylated in hypersexual patients after corrections for multiple testing using the FDR-method. Methylation levels of cg23409074 were positively correlated with gene expression of the CRH gene in an independent cohort of 11 healthy male subjects. The methylation levels at the identified CRH site, cg23409074, were significantly correlated between blood and four different brain regions. CRH is an important integrator of neuroendocrine stress responses in the brain, with a key role in the addiction processes. Our results show epigenetic changes in the CRH gene related to hypersexual disorder in men. (C) 2017 Elsevier Ltd. All rights reserved.

  • 23.
    Jokinen, Jussi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Karolinska Inst, Karolinska Univ Hosp, Dept Clin Neurosci Psychiat, SE-17176 Stockholm, Sweden.
    Chatzittofis, Andreas
    Hellström, Christer
    Nordström, Peter
    Uvnäs-Moberg, Kerstin
    Åsberg, Marie
    Low CSF oxytocin reflects high intent in suicide attempters2012Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 37, nr 4, s. 482-90Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Data from animal studies suggest that oxytocin is an important modulating neuropeptide in regulation of social interaction. One human study has reported a negative correlation between CSF oxytocin levels, life history of aggression and suicidal behaviour. We hypothesized that CSF oxytocin levels would be related to suicidal behaviour, suicide intent, lifetime interpersonal violence and suicide risk. 28 medication free suicide attempters and 19 healthy volunteers participated in this cross sectional and longitudinal study. CSF and plasma morning basal levels of oxytocin were assessed with specific radio-immunoassays. The Beck Suicide Intent Scale (SIS), the Freeman scale and the Karolinska Interpersonal Violence Scale (KIVS) were used to assess suicide intent and lifetime violent behaviour. All patients were followed up for cause of death. The mean follow-up was 21 years. Suicide attempters had lower CSF oxytocin levels compared to healthy volunteers p=0.077. In suicide attempters CSF oxytocin showed a significant negative correlation with the planning subscale of SIS. CSF oxytocin showed a significant negative correlation with suicide intent, the planning subscale of SIS and Freeman interruption probability in male suicide attempters. Correlations between plasma oxytocin levels and the planning subscale of SIS and Freeman interruption probability were significant in male suicide attempters. Lifetime violent behaviour showed a trend to negative correlation with CSF oxytocin. In the regression analysis suicide intent remained a significant predictor of CSF oxytocin corrected for age and gender whereas lifetime violent behaviour showed a trend to be a predictor of CSF oxytocin. Oxytocin levels did not differ significantly in suicide victims compared to survivors. CSF oxytocin may be an important modulator of suicide intent and interpersonal violence in suicide attempters.

  • 24.
    Jokinen, Jussi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Karolinska Institutet, Sweden.
    Chatzittofis, Andreas
    Nordstrom, Peter
    Arver, Stefan
    The role of neuroinflammation in the pathophysiology of hypersexual disorder2016Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 71, s. 55-55Artikel i tidskrift (Övrigt vetenskapligt)
  • 25.
    Jokinen, Jussi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Karolinska Inst, Dept Clin Neurosci, Karolinska Univ Hosp, Psychiat Sect, SE-17176 Stockholm, Sweden.
    Ouda, John
    Karolinska Inst, Dept Clin Neurosci, Karolinska Univ Hosp, Psychiat Sect, SE-17176 Stockholm, Sweden.
    Nordström, Peter
    Karolinska Inst, Dept Clin Neurosci, Karolinska Univ Hosp, Psychiat Sect, SE-17176 Stockholm, Sweden.
    Noradrenergic function and HPA axis dysregulation in suicidal behaviour2010Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 35, nr 10, s. 1536-1542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Noradrenergic and HPA axis dysregulation may play a role in suicide risk. Studies of suicide risk have not found consistent relationship to the noradrenaline metabolite 3-methoxy-4-hydroxphenylglycol (MHPG) in the cerebrospinal fluid (CSF). Non-suppression in the dexamethasone test (DST) has been associated with increased risk of suicide in depressed patients. The study sample consisted of 51 mood disorder inpatients admitted to the Department of Psychiatry at the Karolinska University Hospital between 1980 and 2000. Patients underwent lumbar punction and DST and were followed up for the cause of death. The hypothesis was that both CSF MHPG and HPA axis dysregulation are associated with suicidal behaviour. Nine suicide victims had significantly lower CSF MHPG and baseline plasma cortisol than survivors. Using both CSF MHPG and baseline cortisol in ROC analysis for suicide prediction, the positive predictive value was 44% and the area under the curve was 0.88. In conclusion, lower CSF MHPG was associated with suicide risk. Furthermore these results suggest that combined measures of noradrenergic system and HPA axis function may offer better prediction of suicide risk.

  • 26.
    Kask, Kristiina
    et al.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Gulinello, Maria
    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, USA.
    Sundström-Poromaa, Inger
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women2008Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 33, nr 1, s. 100-107Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: During the postpartum period, estradiol and progesterone levels decline from very high levels during late pregnancy to low levels within 48h of parturition. This period is associated with dysphoric states such as the postpartum blues. Animal studies have suggested an enhanced acoustic startle response and deficient prepulse inhibition (PPI) of startle response following progesterone withdrawal and during the postpartum period. The aim of the current study was to compare acoustic startle response and PPI in healthy third trimester pregnant women and healthy postpartum women. METHODS: Twenty-eight healthy pregnant and 21 healthy postpartum women (examined between 48h and 1 week after delivery) were recruited for the study. In addition, to evaluate the time-course of postpartum changes 11 early postpartum women (examined within 48h following delivery) were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78 or 86dB. RESULTS: Pregnant women exhibited lower levels of PPI compared to late postpartum women, p<0.05. There was no difference between pregnant women and postpartum women examined within 48h of delivery. There was no difference in startle response or habituation to startle response between pregnant women and either of the two groups of postpartum women. CONCLUSION: Healthy women display lower levels of PPI during late pregnancy when estradiol and progesterone levels are high compared to the late postpartum period when ovarian steroid levels have declined.

  • 27.
    Kling, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Mjörndal, Tom
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Glucocorticoid treatment increases density of serotonin 5-HT2A receptors in humans2012Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, nr 7, s. 1014-1020Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Interactions between the serotonergic system and the hypothalamic–pituitary–adrenal axis have been suggested, albeit the details for such interactions have yet to be established. Animal studies have shown that the density of serotonin 5-HT2A receptors is increased after administration of exogenous glucocorticoids.

    Objective: The objective of this study was to explore possible changes in the pattern of density and affinity of 5-HT2A receptors in humans after treatment with glucocorticoids.

    Methods: Using a radioactive binding assay, the density and affinity (measured as Bmax and Kd) of 5-HT2A serotonin receptors were measured in blood samples drawn from 27 individuals diagnosed with polymyalgia rheumatica and/or giant cell arteritis before and after start of an oral treatment with prednisolone. For each patient Bmax and Kd at baseline before prednisolone treatment were compared with Bmax and Kd in samples drawn at a first and second follow-up clinic visit at an average of 8.8 (±2.5) days and 33.6 (±6.8) days, respectively.

    Results: The density of 5-HT2A receptors increased after treatment in 23 individuals. The mean Bmax value at baseline for all patients was 45.2 fmol/mg protein compared with 64.9 fmol/mg protein in the corresponding samples drawn at the second follow-up visit (p = 0.001). There also was an association between individuals accumulated prednisolone dose and the magnitude of change in Bmax between baseline and the first follow-up visit. Erythrocyte sedimentation rate, platelet count or gender had no influence on the results. There were no significant differences in Kd during the treatment period. However, a low Kd value at baseline was a predictor for an increase in Bmax following treatment.

    Conclusions: The results of this study showed that the density of 5-HT2A serotonin receptors in man is increased after a subchronic treatment with glucocorticoids. The magnitude of the increase appears to be associated with the affinity of 5-HT2A receptors before treatment and the accumulated dose of glucocorticoid early in the treatment period.

  • 28. Lundin, Cecilia
    et al.
    Gemzell Danielsson, Kristina
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Moby, Lena
    Bengtsdotter, Hanna
    Jawad, Izabella
    Marions, Lena
    Brynhildsen, Jan
    Malmborg, Agota
    Lindh, Ingela
    Sundström Poromaa, Inger
    Combined oral contraceptive use is associated with both improvement and worsening of mood in the different phases of the treatment cycle: A double-blind, placebo-controlled randomized trial2017Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 76, s. 135-143Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Ever since the introduction of combined oral contraception (COC), one of the major reasons for discontinuing the pill use has been mood-related side effects. Moreover, women who discontinue the pill turn to less effective methods whereby the probability of an unintended conception increases. Approximately 4-10% of COC users complain of depressed mood, irritability or increased anxiety, but drug-related causality has been difficult to prove. Given the lack of randomized controlled trials in this area, we aimed to prospectively estimate the severity of adverse mood in COC users that would be as representative of general users as possible. Methods: This investigator-initiated, multi-center, randomized, double-blinded, placebo-controlled study included 202 healthy women. Women were randomized to a COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo for three treatment cycles. Main outcome measure was the Daily Record of Severity of Problems (DRSP), which was filled out daily during one baseline cycle and the final treatment cycle. Results: Results from 84 women in the COC group and 94 women in the placebo group were analysed. COC use was associated with small, but statistically significant, increases in mean anxiety (0.22; 95% CI: 0.07-0.37, p = 0.003), irritability (0.23; 95% CI: 0.07-0.38, p = 0.012), and mood swings scores (0.15; 95% CI: 0.00-0.31, p = 0.047) during the intermenstrual phase, but a significant premenstrual improvement in depression (-0.33; 95% CI: -0.62 to -0.05, p = 0.049). Secondary analyses showed that women with previous adverse hormonal contraceptive experience reported significantly greater mood worsening in the intermenstrual phase in comparison with healthy women, p <0.05. The proportion of women who reported a clinically relevant mood deterioration did not differ between those allocated to COC (24.1%) or placebo (17.0%), p = 0.262. Conclusion: COC use is associated with small but statistically significant mood side effects in the inter menstrual phase. These findings are driven by a subgroup of women who clearly suffer from COC-related side effects. However, positive mood effects are noted in the premenstrual phase and the proportion of women with clinically relevant mood worsening did not differ between treatment groups.

  • 29.
    Maripuu, Martin Peter
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Wikgren, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Karling, Pontus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Norrback, Karl-Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Relative hypocortisolism is associated with obesity and the metabolic syndrome in recurrent affective disorders2016Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 71, s. 64-65Artikel i tidskrift (Övrigt vetenskapligt)
  • 30.
    Nyberg, Sigrid
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Andersson, Agneta
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Zingmark, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Wahlström, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Sundström-Poromaa, Inger
    The effect of a low dose of alcohol on allopregnanolone serum concentrations across the menstrual cycle in women with severe premenstrual syndrome and controls.2005Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, nr 9, s. 892-901Artikel i tidskrift (Refereegranskat)
  • 31.
    Nyberg, Sigrid
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Wahlström, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Sundström Poromaa, Inger
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Altered sensitivity to alcohol in the late luteal phase among patients with premenstrual dysphoric disorder.2004Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 29, nr 6, s. 767-777Artikel i tidskrift (Refereegranskat)
  • 32.
    Ossewaarde, Lindsey
    et al.
    Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
    Hermans, Erno J
    Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
    van Wingen, Guido A
    Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
    Kooijman, Sabine C
    Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
    Johansson, Inga-Maj
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Fernández, Guillén
    Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
    Neural mechanisms underlying changes in stress-sensitivity across the menstrual cycle2010Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 35, nr 1, s. 47-55Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hormonal fluctuations across the menstrual cycle are thought to play a central role in premenstrual mood symptoms. In agreement, fluctuations in gonadal hormone levels affect brain processes in regions involved in emotion regulation. Recent findings, however, implicate psychological stress as a potential mediating factor and thus, we investigated whether effects of moderate psychological stress on relevant brain regions interact with menstrual cycle phase. Twenty-eight healthy women were tested in a crossover design with menstrual cycle phase (late luteal versus late follicular) and stress (stress induction versus control) as within-subject factors. After stress induction (or control), we probed neural responses to facial expressions using fMRI. During the late luteal phase, negative affect was highest and the stress-induced increase in heart rate was mildly augmented. fMRI data of the control condition replicate previous findings of elevated amygdala and medial prefrontal cortex responses when comparing the late luteal with the late follicular phase. Importantly, stress induction had opposite effects in the two cycle phases, with unexpected lower response magnitudes in the late luteal phase. Moreover, the larger the increase in allopregnanolone concentration across the menstrual cycle was, the smaller the amygdala and medial prefrontal cortex responses were after stress induction in the late luteal phase. Our findings show that moderate psychological stress influences menstrual cycle effects on activity in the emotion regulation circuitry. These results provide potential insights into how fluctuations in allopregnanolone that naturally occur during the menstrual cycle may change stress vulnerability.

  • 33. Ragnarsson, Oskar
    et al.
    Stomby, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Ryhov County Hospital, Jönköping, Sweden.
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Evang, Johan A.
    Ryberg, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Bollerslev, Jens
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Johannsson, Gudmundur
    Decreased prefrontal functional brain response during memory testing in women with Cushing's syndrome in remission2017Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 82, s. 117-125Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neurocognitive dysfunction is an important feature of Cushing's syndrome (CS). Our hypothesis was that patients with CS in remission have decreased functional brain responses in the prefrontal cortex and hippocampus during memory testing. In this cross-sectional study we included 19 women previously treated for CS and 19 commis matched for age, gender, and education. The median remission time was 7 (IQR 6-10) years. Brain activity was studied with functional magnetic resonance imaging during episodic- and working memory tasks. The primary regions of interest were the prefrontal cortex and the hippocampus. A voxel-wise comparison of functional brain responses in patients and controls was performed. During episodic-memory encoding, patients displayed lower functional brain responses in the left and right prefrontal gyrus (p < 0.001) and in the right inferior occipital gyrus (p < 0.001) compared with controls. There was a trend towards lower functional brain responses in the left posterior hippocampus in patients (p = 0.05). During episodic-memory retrieval, the patients displayed lower functional brain responses in several brain areas with the most predominant difference in the right prefrontal cortex (p < 0.001). During the working memory task, patients had lower response in the prefrontal cortices bilaterally (p < 0.005). Patients, but not controls, had lower functional brain response during a more complex working memory task compared with a simpler one. In conclusion, women with CS in long-term remission have reduced functional brain responses during episodic and working memory testing. This observation extends previous findings showing long-term adverse effects of severe hypercortisolaemia on brain function.

  • 34. Stefansson, Jon
    et al.
    Chatzittofis, Andreas
    Nordstrom, Peter
    Arver, Stefan
    Asberg, Marie
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    CSF and plasma testosterone in attempted suicide2016Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 74, s. 1-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Very few studies have assessed testosterone levels in the cerebrospinal fluid in suicide attempters. Aggressiveness and impulsivity are common behavioural traits in suicide attempters. Dual-hormone serotonergic theory on human impulsive aggression implies high testosterone/cortisol ratio acting on the amygdala and low serotonin in the prefrontal cortex. Our aim was to examine the CSF and plasma testosterone levels in suicide attempters and in healthy volunteers. We also assessed the relationship between the testosterone/cortisol ratio, aggressiveness and impulsivity in suicide attempters. 28 medication-free suicide attempters and 19 healthy volunteers participated in the study. CSF and plasma testosterone sulfate and cortisol levels were assessed with specific radio-immunoassays. The Karolinska Scales of Personality was used to assess impulsivity and aggressiveness. All patients were followed up for cause of death. The mean follow-up period was 21 years. Male suicide attempters had higher CSF and plasma testosterone levels than age- matched male healthy volunteers. There were no significant differences in CSF testosterone levels in female suicide attempters and healthy female volunteers. Testosterone levels did not differ significantly in suicide victims compared to survivors. In male suicide attempters, the CSF testosterone/cortisol ratio showed a significant positive correlation with both impulsivity and aggressiveness. Higher CSF testosterone levels may be associated with attempted suicide in young men through association with both aggressiveness and impulsivity, a key endophenotype in young male suicide attempters.

  • 35.
    Wihlbäck, Anna-Carin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Sundström-Poromaa, Inger
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Estradiol and the addition of progesterone increase the sensitivity to a neurosteroid in postmenopausal women2005Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, nr 1, s. 38-50Artikel i tidskrift (Refereegranskat)
  • 36.
    Wihlbäck, Anna-Carin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Sundström Poromaa, Inger
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Allard, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Mjörndal, Tom
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Spigset, Olav
    Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding2004Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 29, nr 6, s. 757-766Artikel i tidskrift (Refereegranskat)
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