| 1. |
- Kaltsouni, Elisavet
(författare)
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Neuroimaging progesterone receptor modulation in patients with premenstrual dysphoric disorder : Is it just in your head?
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Premenstrual dysphoric disorder (PMDD) is a menstrually related mood disorder affecting about 5% of women during their reproductive years. The disorder is cyclic, with the symptomatology namely occurring at the luteal phase of a menstrual cycle, for most ovulatory menstrual cycles and entails a series of mood and physical symptoms. A neural susceptibility to regular hormonal fluctuations is hypothesized as the neuropathophysiological mechanism. While treatment options, such as selective serotonin reuptake inhibitors and hormonal interventions, are available, the neural mechanisms underlying symptom relief remain largely unclear. In this series of studies, a multimodal neuroimaging design was approach was used to reveal the neural correlates of three-month, low-dose selective progesterone receptor modulator (SPRM) treatment in comparison to a placebo. This treatment has been demonstrated to be effective in alleviating psychological symptoms associated with PMDD. Thirty-five women with fulfilling the criteria of a PMDD diagnosis were randomized to treatment with SPRM or placebo, with structural and functional MRI scans conducted before and after randomization. Findings indicated enhanced fronto-cingulate activity during a reactive aggression task in the SPRM treatment group compared to placebo, along with a negative association between aggressive responding and brain activity in the placebo group. Resting state functional connectivity was additionally altered after treatment with SPRM in fronto-visual, temporo-insular, and temporo-cerebellar regions. Additionally, a positive correlation was observed between the reduction in cortisol levels and the decrease in temporo-insular connectivity. No treatment effects were observed on brain structure, including grey and white matter volume, as well as cortical surface architecture. Lastly, White matter microstructure integrity did not differ longitudinally but showed cross-sectional differences. In conclusion, the effects of SPRM treatment were primarily observed in brain function, specifically in terms of enhanced cognitive control processing in the context of reactive aggression and resting state functional connectivity in regions relevant to cognitive and sensorimotor processing, with no significant structural alterations noted. Taken together, these findings confirm that the fluctuations rather than absolute levels of ovarian hormones are primary contributing to premenstrual symptomatology, potentially through hormonal-state dependent functional correlates.
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| 2. |
- Bränn, Emma, 1988-
(författare)
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Biomarkers for Peripartum Depression : Focusing on aspects of the immune system and the metabolome
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peripartum depression is a common, multifactorial, and potentially devastating disease among new mothers. A biological marker for peripartum depression would facilitate early detection, better understanding of the pathophysiology, and identification of targets for treatment. Evidence is growing for a potential role of the immune system in depression outside the peripartum period. Major adaptations of the immune system occur during pregnancy, justifying the search for immunological markers for peripartum depression. The immune system is very complex and dynamic during pregnancy, complicating the study of associations with depression. The metabolome is also affected by pregnancy and is linked to the immune system via, e.g., the microbiota. Hence, metabolomic profiling could increase the understanding of peripartum depression. This thesis aimed to explore inflammatory markers and metabolic profiles in the peripartum period, in order to discover possible biomarkers, and to increase the understanding of the pathophysiology of peripartum depression.All studies were conducted within the Biology, Affect, Stress, Imaging, and Cognition (BASIC) study. The Edinburgh Postnatal Depression Scale and the Mini International Neuropsychiatric Interview were used to assess depressive symptoms. Multiplex Proximity Extension assays were used to analyze inflammatory markers in pregnancy and postpartum. Luminex Bio-Plex Pro Human Cytokine Assays were used to analyze cytokine levels across the peripartum period, and gas chromatography-mass spectrometry metabolomics were used for metabolic profiling. No marker was discriminative enough to be used on its own as a biomarker for peripartum depression. However, several inflammatory markers (such as STAM-BP, TRANCE, HGF, IL-18, FGF-23, and CXCL1) were identified as possible candidates for more advanced diagnostic algorithms. The results further pointed towards the importance of adaptation of the immune system during pregnancy and postpartum, where levels of cytokines such as VEGF-A might have an important role in antenatal and postpartum depression. The results even highlight the importance of examination timing. Lastly, the metabolic profiling suggested different subgroups of women with postpartum depressive symptoms, supporting theories of peripartum depression being a heterogeneous disease in need of subgroup definition.
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| 3. |
- Edvinsson, Åsa, 1982-
(författare)
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Biological Aspects of Peripartum Depression
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peripartum depression affects around 12% of women in pregnancy and postpartum, and about 2–3% of European pregnant women use antidepressants, mostly selective serotonin reuptake inhibitors (SSRIs). An increased risk of poor pregnancy outcomes has been described in women with antenatal depression and SSRI treatment during pregnancy. The biological mechanisms behind these complications are not fully understood and here we investigated several biological correlates of peripartum depression, and discriminated between the effects of antidepressant treatment and depression itself.In Paper I, attentional biases in pregnant and postpartum women were studied by using the Emotional Stroop Task, measuring reaction times to different stimuli. The major finding was shorter reaction times in postpartum depressed women, for emotionally valenced stimuli, which can be interpreted as emotional numbing.In Paper II, peripheral inflammatory markers were assessed by proximity extension assay technology in depressed, SSRI-treated and healthy pregnant women. Lower levels of 23 markers were found in women with antenatal depression, independent of treatment, compared with healthy controls. These findings suggest a dysregulated switch to the anti-inflammatory M2 milieu characterizing a normal third trimester.In Paper III, normal changes in inflammatory markers across pregnancy and postpartum were assessed in healthy pregnant and postpartum women. The majority (41) of the 50 markers that differed between groups were lower postpartum. These results clearly reflect the change in the immune system in pregnancy to postpartum transition.In Paper IV, placental gene and protein expression were investigated and nominally significant findings were noted for serotonin receptor 1A (HTR1A) and neuropeptide Y2 receptor (NPY2R), where women with untreated depression displayed higher gene expression than healthy controls. Protein expression analyses revealed higher levels of HTR1A in placentas from SSRI-treated women, compared with healthy controls and women with untreated depression. This suggests possible involvement of HTR1A in the effect of antenatal depression on the placenta.Overall, peripartum depression is associated with altered cognitive-emotional processing, lower levels of several mostly anti-inflammatory markers, and altered placental gene and protein expression. However, we found no major differences between untreated and treated depression.
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| 4. |
- Nelander, Maria, 1974-
(författare)
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Preeclampsia and the Brain : Epidemiological and Magnetic Resonance Studies
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preeclampsia is a pregnancy specific syndrome that causes substantial maternal and fetal morbidity and mortality. One major contributor to maternal deaths is eclampsia, i.e. when seizures arise in the context of preeclampsia. The pathophysiology of eclampsia is still incompletely chartered and the long-term cerebral consequences of preeclampsia are also largely unknown.This thesis consists of a register based cohort study (n=3232, study I), and a cross-sectional neuroimaging study of pregnant women with and without preeclampsia (n=78, studies II-IV).In paper I, we compared the incidence of dementia and cardiovascular disease (CVD) between women ≥65 years with a self-reported history of hypertensive pregnancy, and women with a normotensive pregnancy. No difference was found regarding dementia, but an increased risk of CVD persisted among these elderly women.In paper II, we used phosphorus magnetic resonance spectroscopy to measure cerebral magnesium levels (Mg2+). We found lower levels of Mg2+ in women with preeclampsia than in women with normal pregnancy and non-pregnant women. Further, which was novel, we showed that lower cerebral Mg2+levels correlated with visual disturbances. The findings are interesting, since magnesium sulfate is the most effective treatment and prophylaxis for eclampsia, but with a largely unknown mechanism of action.In paper III, we measured cerebral organic osmolytes with proton magnetic resonance spectroscopy and found lower levels of osmolytes in pregnancy. Cerebral osmolytes were positively correlated with a decreased plasma osmolality, indicating that there is a joint biological mechanism. The only osmolyte that differed between women with preeclampsia and healthy pregnant women was glutamate. Glutamate is an excitatory neurotransmitter, which also functions as an osmolyte. Thus, lower cerebral glutamate levels could have implications on the pathophysiology of seizures.In paper IV, cerebral perfusion and edema were assessed with magnetic resonance imaging using intravoxel incoherent motion technique. A reduced perfusion fraction was found in a part of the basal ganglia in women with preeclampsia. No difference in edema was detected.Our findings indicate Mg2+ metabolism, plasma hypoosmolality and possibly cerebral hypoperfusion to be involved in the pathophysiology of cerebral affection in preeclampsia.
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| 5. |
- Valgeirsdóttir, Heiddis, 1982-
(författare)
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Polycystic Ovary Syndrome and Pregnancy : Prenatal Exposures and Pregnancy Complications
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of fertile age. The aetiology of PCOS is not fully understood and might be affected by foetal exposures. Women with PCOS have an increased risk of pregnancy complications, but information on rare severe complications is scarce.The overall aim of this thesis was to gain further knowledge of the association between the intrauterine environment and development of PCOS in offspring, and the association between maternal PCOS and adverse pregnancy outcomes, with a focus on preterm birth and stillbirth.This thesis includes three nationwide register-based cohort studies and one matched cohort study including early second-trimester blood samples. Associations were estimated with multivariate Cox, logistic and linear regression models, with adjustment for confounders including body mass index. Correlations were estimated with Spearman’s rank correlation coefficient.It was found that maternal overweight and obesity, and smoking during pregnancy, were associated with increased risk for female offspring to develop PCOS later in life compared with offspring of normal weight and non-smoking mothers, respectively. Size at birth was not associated with the risk of PCOS development. During pregnancy, women with PCOS had higher second-trimester levels of anti-Müllerian hormone (AMH) and testosterone than non-PCOS women, and AMH levels were positively correlated with total testosterone levels. High AMH levels were not associated with an increased risk of pregnancy complications. Women with PCOS seemed at increased risk of extremely, very, and moderately preterm birth compared with non-PCOS women. The association was strongest for extremely preterm birth of spontaneous onset. Women with PCOS also seemed at increased risk of stillbirth compared with non-PCOS women, and the rate of stillbirth in PCOS women was particularly high in term pregnancy.In conclusion, increased maternal BMI and maternal smoking may increase the risk of PCOS in offspring. Even though second-trimester AMH levels are higher in pregnant women with PCOS than controls, AMH seems not to be a mediator of increased risk for pregnancy complications in PCOS women. PCOS should be considered a risk factor for severe pregnancy complications such as extremely preterm birth and stillbirth.
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| 6. |
- Dubol, Manon, et al.
(författare)
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Acute nicotine exposure blocks aromatase in the limbic brain of healthy women : A [11C]cetrozole PET study
- 2023
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Ingår i: Comprehensive Psychiatry. - : Elsevier. - 0010-440X .- 1532-8384. ; 123
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Tidskriftsartikel (refereegranskat)abstract
- Background: Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain.Methods: The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI -based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential.Results: The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d =-0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend.Conclusions: These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.
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| 7. |
- Kaltsouni, Elisavet, et al.
(författare)
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Selective progesterone receptor modulation and brain activity at rest in patients with premenstrual dysphoric disorder
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian hormones have been indicated to impact brain connectivity and mood. However, there is no consistent evidence on hormone-dependent functional connectivity and mental health. Alterations in resting state networks have been suggested as markers of affective disorders, but only preliminary evidence is provided on premenstrual dysphoric disorder, in which symptoms occur upon fluctuations of ovarian hormones. Recently, three-month low-dose selective progesterone receptor modulator (SPRM) administration has been associated with symptom relief and altered task-based brain reactivity during a reactive aggression condition. The present study sought to investigate the effect of this treatment on resting state functional connectivity (rs-FC) in patients with PMDD. Seed-based analyses were conducted, including including seeds from the classic resting state networks along with the functional cluster affected by SPRM treatment. Within previously identified networks related with emotional processing, rs-FC was compared between individuals with PMDD during the symptomatic luteal phase before randomization to treatment or placebo and during the end of the last treatment cycle. Seed-based rs-FC analyses yielded significant treatment by time effects on rs-FC between the left posterior superior temporal gyrus and the right insula cortex, between the posterior cerebellum and the left temporal pole, and between the right lateral visual network and left superior frontal gyrus. Visuo-frontal luteal phase connectivity decreased for the SPRM group and was positively correlated with changes in mood symptom severity in the placebo group. Cerebellar and temporal connectivity increased for the SPRM treatment group, while temporo-insular connectivity decreased and was positively correlated with cortisol levels. These findings indicate that SPRM treatment influenced rs-FC, which could be a relevant mechanism behind symptom alleviation.
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| 8. |
- Kaltsouni, Elisavet, et al.
(författare)
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White matter integrity upon progesterone antagonism in individuals with premenstrual dysphoric disorder: a randomized placebo-controlled diffusion tensor imaging study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Premenstrual dysphoric disorder (PMDD) is a depressive disorder triggered by fluctuations of progesterone and estradiol during the luteal phase of the menstrual cycle. Selective progesterone receptor modulation (SPRM), while exerting an antagonistic effect on progesterone and maintaining the estradiol on moderate levels, has shown beneficial effects on the mental symptoms of PMDD. Progesterone is also known for its neuroprotective effects, while synthetic progestins have been suggested to promote myelination. However, the impact of this treatment on white matter neuroanatomy is unexplored. Diffusion tensor imaging was used to collect data on white matter integrity in patients with PMDD, before and after treatment with ulipristal acetate (an SPRM) or placebo, as part of a double-blind randomized controlled-trial. Tract based spatial statistics were performed to investigate SPRM treatment vs. placebo longitudinal effects on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) on the whole white matter skeleton. Voxel-wise analyses indicated no change over time in any white matter microstructure metrics in individuals treated with SPRM versus placebo. Improvement in PMDD symptoms did not correlate with changes in white matter microstructure. In secondary, cross-sectional comparisons during treatment, the SPRM group displayed lower FA and higher MD, RD, and AD in several tracts. The main findings suggest that SPRM treatment did not impact white matter microstructure. However, the between-group differences after treatment call for further investigation on the tracts potentially impacted by progesterone antagonism.
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| 9. |
- Kaltsouni, Elisavet, et al.
(författare)
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White matter volume and treatment with selective progesterone receptor modulator in patients with premenstrual dysphoric disorder
- 2024
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 163
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Tidskriftsartikel (refereegranskat)abstract
- Premenstrual dysphoric disorder (PMDD) is a mood disorder for which selective progesterone receptor modulator (SPRM) treatment has been demonstrated to be beneficial. The neural signatures of this treatment have been so far identified as greater fronto-cingulate reactivity during aggressive response to provocation, but no changes in terms of gray matter structure. White matter has recently been found to differ between patients with PMDD and healthy controls. The present study thus sought to investigate the relationship between white matter volume and SPRM treatment in patients with PMDD. A pharmaco-neuroimaging study was conducted on patients with PMDD participating in a randomized controlled trial. Participants underwent magnetic resonance imaging before and after treatment randomization to ulipristal acetate (an SPRM), or placebo, for three months. The interaction effect of treatment by time on white matter volume (WMV) was assessed. Voxel based morphometry analyses were performed on both a whole brain exploratory level and on regions of interest. No treatment effect was observed on WMV in any region, including the anterior thalamic radiations, cingulum, forceps minor, fornix, inferior fronto-occipital fasciculus, superior cerebellar peduncle, superior longitudinal fasciculus, and uncinate fasciculus. This is the first finding to indicate that no white matter volume alterations follow three-month progesterone antagonism, suggesting that white matter volume does not participate in symptom relief upon SPRM treatment for PMDD.
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| 10. |
- Persson, Sofia, 1985-
(författare)
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Polycystic ovary syndrome : Long-term health aspects
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age, affecting many aspects of women’s health such as fertility, cardiovascular health and quality of life. However, less is known about later life stages, as well as the impact of hyperandrogenism and PCOS itself, apart from risks associated with excess body weight. The overall aim with this thesis was therefore to study how PCOS, and its hyperandrogenic phenotype, is associated with general health, with focus on diabetes, hypertension, dyslipidaemia and fertility at a longer span of time than during the fertile period.Studies I-III were register-based cohort studies, linking six Swedish national registers. In total, >50 000 women with PCOS and ≈ 250 000 controls were included and followed up for up to 20 years. Study IV was a clinical cross-sectional study including 124 women with PCOS and 74 controls.The main results were that PCOS has a great impact on women’s lives extending beyond the fertile period. While women with PCOS achieve a first childbirth as often as non-PCOS women, they have fewer children overall and give birth at a later age. In addition, PCOS is a moderate risk factor for type 2 diabetes, hypertension and dyslipidaemia, regardless of body weight. The risk appears to be more pronounced in those with the hyperandrogenic phenotype. Finally, hyperandrogenism persists largely in midlife for women with PCOS, both through ongoing symptoms such as hirsutism and by having a negative impact on the women’s quality of life.In conclusion, women with PCOS should be informed that they have a good chance of conceiving, but that some may need assisted reproduction. We suggest that PCOS in general and the hyperandrogenic phenotype in particular be included as independent risk factors when counselling women on their likelihood to suffer from cardiovascular disease and its risk factors in particular such as type 2 diabetes, hypertension and dyslipidaemia.
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