| 1. |
- Wallin Lundell, Inger, 1958-
(författare)
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Induced Abortions and Posttraumatic Stress - Is there any relation? : A Swedish multi-centre study
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Induced abortion is a common medical intervention. Whether psychological sequelae might follow induced abortion has long been a subject of concern among researchers, and there is lack of knowledge about the relationship between posttraumatic disorder (PTSD) and induced abortion. Aims: To study and compare PTSD, posttraumatic stress symptoms (PTSS) and anxiety- and depressive symptoms among women seeking abortion, allowing for demographic variables. Further aims were to assess risk factors and to assess PTSD and PTSS following induced abortion in relation to experienced care at the clinic. Methods: This was a multi-centre cohort study targeting women who requested an induced abortion at the outpatient clinics of the gynaecology and obstetrics departments of six public hospitals in Sweden. All women who requested an induced abortion before the end of gestational week 12 were approached for participation. PTSD, PTSS, anxiety- and depressive symptoms, personality traits and women’s perceptions of abortion care were measured by means of questionnaires. Measurements were made at the first visit before the abortion as well as three- and six-months thereafter. Data collection was performed from September 2009 to January 2011. Results: 1,514 women filled out the questionnaire before the abortion. Abortion-seeking women did not suffer from PTSD to a greater extent than the general Swedish female population. Few women (51/720) developed PTSD or PTSS after the abortion, 11 did so due to trauma experience related to the abortion. Women at risk of posttraumatic stress were more likely to be young, having anxiety- or depressive symptoms and personality traits related to neuroticism. Furthermore, women with PTSD or PTSS were more likely to perceive certain aspects of the abortion care as deficient. Conclusions: The vast majority of women coped well with the induced abortion. Few developed posttraumatic stress post abortion. The majority did so because of trauma experiences unrelated to the induced abortion. Young women and women with mental distress are vulnerable groups that need to be paid attention to in abortion care. These women are at risk for negative experiences of the abortion care, and may be at risk of PTSD or PTSS post abortion
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| 2. |
- Bannbers, Elin, 1984-
(författare)
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The Effect of Steroid Hormones in the Female Brain During Different Reproductive States
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Women are twice as likely as men to suffer from depression and anxiety disorders and have an increased risk of onset during periods associated with hormonal changes, such as the postpartum period and the menopausal transition. Furthermore, some women seem more sensitive to normal hormone fluctuations across the menstrual cycle, since approximately 3-5% suffers from premenstrual dysphoric disorder (PMDD). Why these disorders are so common in women has not been established but there is a probable involvement of the ovarian hormones.The aim of this thesis was to investigate the effect of the ovarian hormones on the female brain during different reproductive states using psychological tests known to affect brain activity in different ways.Paper one examined the effect of the ovarian hormones on prepulse inhibition (PPI) on the acoustic startle response (ASR) and comprised cycling women and postmenopausal women. The cycling women had lower levels of PPI compared to postmenopausal women and postmenopausal women with moderate estradiol levels had lower PPI compared to postmenopausal women with low estradiol levels.Paper two examined the effect of anticipation and affective modulation on the ASR in women with PMDD and healthy controls. Women with PMDD have an increased modulation during anticipation of affective pictures compared to healthy controls during the luteal phase of the menstrual cycle.Paper three examined brain activity during response inhibition among women with PMDD and healthy controls by the use of a Go/NoGo task and fMRI. Women with PMDD displayed a decreased activity in the left insula during follicular phase and an increased activity during the luteal phase compared to controls.Paper four comprised women in the postpartum period and non-pregnant controls to examine brain activity during response inhibition. While this study revealed decreased activity at 4 weeks postpartum compared to 48 hours postpartum we cannot ascertain the role of the ovarian steroids, since none of the significant brain areas correlated with ovarian steroid or neurosteroid serum concentrations.The results of this thesis demonstrate that the ovarian hormones, or at least various hormonal states, have a probable impact on how the female brain works.
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| 3. |
- Bolin, Marie
(författare)
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Pre-eclampsia – Possible to Predict? : A Biochemical and Epidemiological Study of Pre-eclampsia
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. A predictor of pre-eclampsia would enable intervention, close surveillance and timely delivery, and thereby reduce the negative consequences of the disorder.The overall aim of this thesis was to study potential predictors of pre-eclampsia by biochemical and epidemiological methods.Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are regulators of angiogenesis, which is important for placental development. In a prospective and longitudinal study of a low-risk population the Ang-1/Ang-2 ratio was evaluated. The Ang-1/Ang-2 ratio increased during pregnancy in all women but at gestational week 25 and 28 the ratios were significantly lower in women who later developed pre-eclampsia. The relevance of Histidine-rich glycoprotein (HRG), a protein with angiogenic properties, was furthermore evaluated. HRG levels decreased in all women, with significantly lower levels at gestational week 10, 25 and 28 in women who later developed pre-eclampsia. Thus both Ang-1/Ang-2 ratio and HRG may predict pre-eclampsia.To evaluate the predictive value of HRG in combination with uterine artery Doppler early in pregnancy a study was performed in a high-risk population. The results revealed that the combination was better able to predict preterm pre-eclampsia than each marker individually, with a sensitivity of 91% at a specificity of 62%. A possible association between hyperemesis gravidarum and pre-eclampsia, as well as other placental dysfunctional disorders, was investigated. Hyperemesis gravidarum may be caused by high levels of human chorionic gonadotrophin (hCG) and increased levels of hCG in the second trimester is associated with later development of pre-eclampsia. A cohort of all pregnancies in the Swedish medical birth register between 1997 and 2009 was studied. After adjustment for confounding factors an association between hyperemesis gravidarum in the second trimester and preterm pre-eclampsia, placental abruption and infants born small for gestational age was demonstrated.In conclusion, the ratio of Ang-1/Ang-2 as well as HRG in plasma may be potential predictors of pre-eclampsia. Combination with uterine artery Doppler further increases the predictive value of HRG for preterm pre-eclampsia. Hyperemesis gravidarum in the second trimester may be considered as a clinical risk predictor of pre-eclampsia and other placental dysfunctional disorders.
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| 4. |
- 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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| 5. |
- Dabo Pettersson, Fatimah, 1975-
(författare)
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Genetics and Labor Pain Behavior
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Labor may perhaps be the most painful a woman might experience, although characterized by large inter-individual variability. The perceived pain during labor is the result of diverse factors, i.e. her previous pain experiences, the analgesia she receives and maybe also her genes. The overall aim of this thesis was to investigate biological and psychological mechanisms underlying inter-individual differences in labor pain related behaviors. The mechanisms that characterize endogenous pain relief during labor are not fully understood, though it is known to be partly explained by the effects of β-endorphin (BE). BE plasma levels were followed longitudinally in a cohort of pregnant women and were found to remain unchanged between early and late pregnancy, although with a nadir in the beginning of the third trimester. Furthermore, women with low levels of BE in plasma at the end of the third trimester, required second line labor analgesia to a significantly higher extent than women with normal levels. In a population-based sample of 814 pregnant women we investigated if inter-individual differences in labor pain related behavior was influenced by the pain-protective single nucleotide polymorphism (SNP) combination of guanosine triphosphate cyclohydrolase (GCH1) and the opioid receptor µ-1 gene (OPRM1) A118G SNP. We identified a possible association between the pain-protective SNP combination of GCH1 and use of second line analgesia. No association was found between the OPRM1 and use of analgesia or labor pain related behavior. The association between self-rated antenatal depressed mood and anxiety in relation to pain behaviors and self-reported pain during labor was investigated. We found that depressed mood during pregnancy is associated with early arrival to the delivery department, whereas antenatal anxiety is associated with increased self-rated pain prior to labor analgesia. In conclusion, although an increasing number of studies strongly suggest that genetic predisposition plays an important role in pain and pain-related mechanisms, GCH1 and OPRM1 has little to offer in terms of individual counseling on labor analgesia. To enable the future use of genetic variability for pre-labor testing and counseling, a number of different genes reflecting pain mediation pathways, involving biological and psychological mechanisms, need to be analyzed in combination.
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| 6. |
- 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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| 7. |
- Kaihola, Helena, 1969-
(författare)
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The Effects of SSRI Treatment on Human Placenta and Embryo
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During pregnancy, 4 - 7% of women suffer from major depressive disorder. When antidepressive treatment is needed, selective serotonin reuptake inhibitors (SSRIs) are the most commonly used. Although severe complications from SSRI treatment are rare, association with a number of adverse pregnancy and fetal outcomes has been found. Also, antenatal depression per se has been shown to affect pregnancy outcomes. The overall aim of this thesis was to examine the effects of SSRIs on human placenta and embryo.In the first study, gene expression was investigated in placenta from depressed, SSRI-treated and healthy pregnant women, using microarray analysis. Antenatal depression and SSRI treatment induced alterations in gene expression, but only 20 genes in common were noted. Validation with qRT-PCR showed that six out of seven selected genes were altered in SSRI-treated women compared with controls, and two genes were altered between depressed women and controls.In study two, the protein levels in placenta from depressed, SSRI-treated and healthy pregnant women were investigated, focusing on the NGF signaling pathway. NGF, phosphorylated Raf-1, ROCK2 and phosphorylated ROCK2, were altered in both SSRI-treated and depressed women, although the proteins were regulated differently in the two groups.In the third study, human embryos were treated with fluoxetine. Embryo development and protein expression were studied. Fluoxetine had some effect on the timing of embryo developmental stages. Also, several proteins were uniquely found in fluoxetine-treated embryos compared with untreated embryos. Fluoxetine also altered the levels of proteins secreted from the embryo.In the fourth study, the human neuroblastoma cell line SH-SY5Y/TrkA was treated with TPA and NGF. The activation of Raf-1 was investigated and the involvement of Ras and PKC was studied. Both NGF and TPA activated Raf-1, but to a different extent and via different pathways. The NGF-induced activation of Raf-1 was mediated via Ras, while TPA induced signaling via PKC.In conclusion, SSRI treatment and antenatal depression influence placental gene and protein expression. These findings may affect placental development and function, which in turn could affect fetal development. Also, direct exposure of embryos to fluoxetine has some effects on embryo development and protein expression, which may affect the development of the fetus.
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| 8. |
- 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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| 9. |
- Kask, Kristiina, 1971-
(författare)
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Hormones, Mood and Cognition
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian steroid hormones are neuroactive steroids with widespread actions in the brain, and are thus able to influence mood, behavior and cognition. In this thesis the effects of progesterone withdrawal and the direct effects of the progesterone metabolite allopregnanolone are evaluated. Allopregnanolone, through binding to the GABAA receptor complex, enhances inhibitory neurotransmission, thus exerting anxiolytic, sedative and antiepileptic effects. The acoustic startle response (ASR) is a withdrawal reflex evoked by sudden or noxious auditory stimuli, and can be measured in humans as an eye blink. ASR is significantly increased in several anxiety disorders, and notably also during progesterone withdrawal. Sensorimotor gating can be assessed by measuring prepulse inhibition of the startle response (PPI). The CNS circuits regulating PPI are sensitive to hormone fluctuations. GABAergic drugs are involved in cognitive impairment and animal studies have indicated that allopregnanolone may inhibit learning.The main purpose of this research was to evaluate the behavioral effects of progesterone withdrawal on the startle response and sensorimotor gating in PMDD patients and healthy controls, in healthy third trimester pregnant women and healthy postpartum women. A second aim was to evaluate allopregnanolone effects on memory and cognition in healthy women and also on the startle response and PPI. We found that PMDD patients have an increased startle response across the menstrual cycle and a deficiency in sensorimotor gating during the late luteal phase. Ovarian steroids affect sensorimotor gating; pregnant women have lower levels of PPI than late postpartum women. Acutely administered allopregnanolone did not affect the ASR or PPI. Allopregnanolone impairs episodic memory in healthy women.In conclusion, our studies suggest that ovarian steroids, including allopregnanolone, do not influence the startle response. Ovarian steroids affect sensorimotor gating; pregnancy, a condition with high levels of ovarian steroids, suppresses PPI. Theoretically, the variability in PPI across reproductive events is due to effects mediated by the progesterone or estradiol receptors but is not mediated by allopregnanolone. PMDD patients display decreased PPI during the late luteal phase, suggesting underlying pathophysiology in common with other anxiety disorders. The most vulnerable memory system, the episodic memory, is impaired by the allopregnanolone in healthy women.
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| 10. |
- Kunovac Kallak, Theodora, 1985-
(författare)
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Hormonal Regulation of Vaginal Mucosa
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vaginal atrophy symptoms such as dryness, irritation, and itching, are common after menopause. Vaginal estrogen therapy is the most effective treatment but not appropriate for all women. Women with estrogen-responsive breast cancer treated with aromatase inhibitor (AI) treatment, suppressing estrogen levels, often suffer from more pronounced vaginal atrophy symptoms. However, vaginal estrogen treatment is not recommended, leaving them without effective treatment options. The aim of this thesis was to study the effect of long-term anti-estrogen therapy on circulating estrogen levels and biochemical factors in vaginal mucosa in relation to morphological changes and clinical signs of vaginal atrophy.Circulating estrogen levels were analyzed by use of mass spectrometry and radioimmunoassay. Immunohistochemistry was used to study vaginal proliferation and steroid hormone receptors in vaginal mucosa. Vaginal gene expression was studied by use of microarray technology and bioinformatic tools, and validated by use of quantitative real-time PCR and immunohistochemistry. An estrogenic regulation of aquaporins and a possible role in vaginal dryness was investigated in vaginal mucosa and in Vk2E6E7 cells.Aromatase inhibitor-treated women had higher than expected estradiol and estrone levels but still significantly lower than other postmenopausal women. Aromatase was detected in vaginal tissue, the slightly stronger staining in vaginal mucosa from AI-treated women, suggest a local inhibition of vaginal aromatase in addition to the systemic suppression. Vaginal mucosa from AI-treated women had weak progesterone receptor, and strong androgen receptor staining intensity. Low estrogen levels lead to low expression of genes involved in cell adhesion, proliferation, and differentiation as well as weak aquaporin 3 protein immunostaining.The higher than expected estrogen levels in AI-treated women suggest that estrogen levels might previously have been underestimated. Systemic estrogen suppression by treatment with AIs, and possibly also by local inhibition of vaginal aromatase, results in reduced cell adhesion, proliferation, differentiation, and weak aquaporin 3 protein staining. Low proliferation and poor differentiation leads to fewer and less differentiated superficial cells affecting epithelial function and possibly also causing vaginal symptoms. Aquaporin 3 with a possible role in vaginal dryness, cell proliferation, and differentiation should be further explored for the development of non-hormonal treatment options for vaginal symptoms.
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