| 1. |
- Bendix, Marie, 1971-
(författare)
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Neuroendocrine studies in patients with affective disorders
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Affective disorders are common and a major cause for increased disability and mortality worldwide. Exogenous stressors and biological variables, including neuroendocrine factors, are assumed to contribute to an increased vulnerability to mood dysregulation. Affective disorders are highly heterogeneous and different neuroendocrine systems may play differential roles in the phenotypic expression of affective disorders in men and women.Aims: The overall aim of this thesis was to study three neuroendocrine systems in relation to underlying behavioral endophenotypes (personality traits, self-directed and interpersonal violence, and psychiatric symptoms) in patients with affective disorders.Methods: In Study I oxytocin plasma levels were assessed in 101 general psychiatric outpatients and followed-up in 36 patients after one month. Patients underwent diagnostic, symptomatic, and personality trait assessments.In Study II insulin and glucagon levels in plasma and cerebrospinal fluid (CSF) were assessed in 28 patients hospitalized after a recent suicide attempt and 19 healthy controls. Study persons were assessed regarding lifetime violence expression, psychiatric diagnoses and symptoms.In Study III serum levels of allopregnanolone, progesterone and estradiol were assessed in 14 women with severe postpartum depression and psychosis who, as previously reported, responded with rapid symptom remission during sublingual estradiol treatment. Hormonal and symptomatic assessment were performed before and after 4 weeks of estradiol treatment. 28 healthy postpartum controls were included for baseline comparison.Results: I) Plasma oxytocin levels were positively associated with personality traits of impulsiveness (monotony avoidance) and negative emotionality (psychic anxiety) with potential gender differences.II) Patients after suicide attempt had higher insulin (plasma and CSF) and lower glucagon levels (CSF) than healthy controls. Insulin levels (plasma and CSF) were higher and glucagon levels (plasma) were lower in patients and controls with higher levels of prior violence expression.III) Serum allopregnanolone decreased in women with postpartum depression and psychosis during estradiol treatment. The ratio between allopregnanolone and progesterone was significantly lower in patients than in healthy controls at baseline and it remained unchanged after symptom remission.Conclusion: Behavioral endophenotypes, rather than categorical diagnoses, of affective disorders were associated with neuroendocrine variation in three different cohorts of patients with affective disorder. Hormonal variation pointed towards an association with trait, rather than state like facets of affective behavior, constituting potential vulnerability markers for affective dysregulation.
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| 2. |
- Hedström, Helena
(författare)
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GABA-steroid effects in healthy subjects and women with polycystic ovary syndrome
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The progesterone metabolite allopregnanolone is involved in several clinical conditions in women, e.g. premenstrual dysphoric disorder. It is a very potent GABA-steroid with GABA-A receptor effects similar to other GABA-agonists, e.g. benzodiazepines, and it causes sedation. An objective way to examine effects on the GABA-A receptor in humans is to measure saccadic eye velocity (SEV), which is reduced by GABA-agonists, e.g. allopregnanolone. Animal studies suggest that allopregnanolone is involved in the regulation of gonadotropin secretion via the GABA-A receptor, but this has not been studied in humans. Polycystic ovary syndrome (PCOS) is the most common endocrine disturbance among women of fertile age (5–10%), characterized by polycystic ovaries, menstrual dysfunction, hyperandrogenity, and 50% have obesity. Studies have shown higher allopregnanolone levels in overweight people. PCOS women have increased levels of androstanediol, an androgen metabolite which is an GABA-A receptor agonist. Tolerance often occurs when persons are exposed to high levels of GABAergic modulators. It has not been studied whether GABA-A receptor sensitivity in PCOS women is changed. Another progesterone metabolite, isoallopregnanolone, is the stereoisomere of allopregnanolone but has not been shown to have any GABA-A receptor effect of its own. Instead it has often been used to control steroid specificity to allopregnanolone. Aims: To compare the effects of allopregnanolone and isoallopregnanolone on gonadotropin secretion. To compare allopregnanolone levels, GABA-A receptor sensitivity to allopregnanolone and effects on gonadotropin secretion in both cycle phases and PCOS conditions. To examine pharmacokinetics and pharmacodynamic properties for isoallopregnanolone. Method: In the follicular phase healthy women were examined for the effect of allopregnanolone or isoallopregnanolone on gonadotropin secretion. PCOS women and healthy women in both cycle phases were given allopregnanolone and the differences in effects on SEV were examined, as well as changes in serum levels of gonadotropins and allopregnanolone at baseline and during the test day. Pharmacokinetics and GABA-A receptor sensitivity using SEV were explored for isoallopregnanolone in healthy women. Results: Allopregnanolone decreases gonadotropin serum levels in healthy controls in both cycle phases, but has no effect on gonadotropin secretion in women with PCOS. PCOS women have higher baseline serum levels of allopregnanolone than follicular phase controls, but lower levels than luteal phase controls. PCOS women show greater reduction in SEV to allopregnanolone than controls. Isoallopregnanolone has no effect on gonadotropin secretion. There is an effect of isoallopregnanolone on SEV, explained by a metabolism of isoallopregnanolone into allopregnanolone. Conclusion: There are significant differences in the GABA-A receptor response to a GABA-steroid in different endocrine conditions in women of fertile age examined with saccadic eye velocity. The GABA-steroid allopregnanolone decreases gonadotropin serum levels in healthy women but not in PCOS women. The lack of effect on gonadotropins by isoallopregnanolone suggests an involvement of the GABA-A receptor.
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| 3. |
- Lundin, Cecilia
(författare)
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Hormonal contraception, mood and sexual function
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hormonal contraceptives (HCs) are used by millions of women worldwide. Apart from their contraceptive effect, they also offer additional health benefits such as decreased menstrual bleedings and amelioration of menstrual-related pain. Adverse mood and sexual side-effects during HC-use are commonly reported, and women who discontinue treatment with HCs often claim these side effects as reason for cessation.Although several studies have investigated associations of HCs and adverse mood and sexual side-effects, little is known about causally drug-related outcomes. Few randomised controlled trials (RCTs) have been conducted, and observational studies in the field are subject to several methodological caveats which limit what conclusions that can be drawn from them.The overall aim of this thesis was to investigate the effect of HCs on various aspects of mood and sexual function.Study one was a randomised controlled trial where participant women received a combined oral contraceptive (COC) or placebo. Mood and sexual function were assessesed through daily ratings and questionnaires and measured at baseline and after three months treatment. Study two was a cross-sectional study that assessed which demographic, reproductive, and psychiatric factors are associated with self-reported HC-induced adverse mood symptoms.Study three was a register-based cohort study including all Nordic-born women aged 15-24 residing in Sweden between 2010 and 2017. Risk of depression – captured as redeemed prescription of antidepressant treatment or a depression diagnosis – among HC-users compared to non-users were estimated. Women who were randomised to a COC reported increased anxiety, mood swings and irritability compared to women randomised to placebo. In contrast, women who received a COC improved in depressive symptoms (paper I). Compared to women randomised to placebo, women who received a COC deteriorated regarding sexual interest and vaginal lubrication. Only deterioration in sexual interest remained after adjustments for depressive symptoms (paper II). Compared to women with no self-reported HC-induced adverse mood symptoms, women with such experience more often suffered from an ongoing minor depressive disorder, had more often experienced any previous mental health problem, and had more often undergone induced abortion (paper III). No uniform associations between use of HCs and subsequent risk of depression were found. In general, oral contraceptives conferred lower or no risk, while non-oral contraceptives were associated with small increased risks. Higher risks were found among HC-users aged 15-19 years compared to older HC-users (paper IV).
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| 4. |
- Nüssler, Emil, 1990-
(författare)
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Vaginal prolapse surgery : an epidemiological perspective : studies of native tissue repair versus implants, surgeons´ practical experiences and five year follow-up in the swedish national quality register for gynecological surgery
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Pelvic organ prolapse (POP) is a common condition that impacts on quality of life for many women. The mean age of Swedish women operated for POP is 60 years, and with a life expectancy of approximately 84 years this means that the average patient will live 24 years subsequent to the operation. Therefore, sustainable long-term results of POP surgery are essential. In an effort to improve long-term outcomes of vaginal prolapse surgery, mesh materials have been developed for this purpose. In Sweden, synthetic mesh is used in 7.4% of all primary operations without any coherent consensus about their use. Prolapse surgery is regarded as a routine procedure performed at almost every hospital in Sweden, but a large proportion of the surgeons are inexperienced. In actuality, 73% of them perform the procedure once a month or less frequently. Simultaneously, surgery for POP has been reported to have a highfailure rate internationally. For most surgeons, the operation is a low-frequency procedure, and outcomes have been reported as unsatisfactory. The specific aims of these thesis were to examine:- Mesh-augmented repairs impact on operative results compared to nativetissue repair.- Surgical experience in performing a specific operation and utilize this knowledge in analysing how it may (or may not) affect operative results.- Long-term (5 year) national follow up of POP operations, regarding both the objective epidemiological data and the patient-reported outcomes.Methods: The studies in this thesis are based on data from the Swedish National Quality Register for Gynaecological Surgery (GynOp), which covers approximately 90% of all gynaecological operations in Sweden. The comparative follow-up of POP surgery using non-absorbable polypropylene mesh versus colporrhaphy using native tissue was analysed in two different cohorts, of women with a primary cystocele and women with a relapse after surgery for a rectocele. Both surgeon reported results and patient-reported outcomes (PROMs) were analysed 1 year post-surgery. Information about surgeons’ experience in performing POP operations was extracted from GynOp over 9 years. Inclusion criteria were otherwise healthy patients who underwent anterior or posterior native tissue repair, or both. The operations were divided into four groups according to the operative experience of the surgeon (measured as average number of operations per active year). Both PROM results and surgeon-reported outcomes after 1 year were investigated. For the long-term follow-up 5 years after any operation for a vaginal prolapse, a new questionnaire to capture PROM data was designed, validated and nationally distributed. Information about re-operations was extracted directly from GynOp.Results: Mesh-augmented repair of a primary cystocele had a significantly better outcome in terms of absence of symptoms, compared with native tissue repair, OR 1.53(95% CI 1.10-2.13), but also had more complications directly related to the procedure (OR 1.51, RD=6.6%). For recurrent rectocele, mesh was superior to native tissue repair, OR 2.06 (95% CI 1.03-4.35); the number of postoperative complications was equal in the two groups. Among the 1,092 surgeons who were active POP surgeons during the study, 803(73%) participated in POP operations once a month or less frequently in their active years. No differences in patient or surgeon-reported outcomes were seen between the “experience groups”. Kaplan-Meier curves for re-operation after a primary POP operation showed an overall retreatment rate of 11.2% after 5 years. The response rate for the patient questionnaire was 74.9%. Overall, 70% of the patients reported no symptoms, and around 72% and 82% were satisfied with the operative results and felt that their symptoms had improved, respectively.Discussion: Mesh use was, after 1 year of follow-up, generally characterized by a high cure rate and varying degrees of complications, such as postoperative pain. However, for recurrent rectocele, we found no immediate drawbacks of the method compared with native tissue repair, with the same high cure rate as seen in other compartments. Surgeon experience had no impact on the native tissue operation, and any inconsistency of outcome is more likely inherent in the method than attributable to a surgeon’s lack of experience.The 5-year results indicate that native tissue repair produces much better results, judging from overall Swedish results, than previously thought. This is backed up both by objective data indicating a minimal number of re-operations within 5 years for the most common cases (i.e. primary rectocele and cystocele) and by the outcomes reported by the patients themselves.Conclusions: Mesh-augmented repair is more effective than native tissue repair forrecurrent rectocele, and without increased risk of complications. Drawbacks of mesh repair vary for other compartments, and for primary operations.- Surgeons’ operative experience in routine POP operations using native tissue has no impact on outcome after 1 year.- Long-term results of POP repair with native tissue are excellent, with a low risk of re-operation and a persistent absence of subjective symptoms.
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| 5. |
- Segebladh, Birgitta, 1956-
(författare)
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Is it Just the Hormones? : Sex Steroids, Chronic Stress and Violence in Premenstrual Dysphoric Disorder
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Premenstrual depressive symptoms and mood swings affect 3-8% of women in fertile age. The female hormones are believed to be the cause. Progesterone is well studied, but estrogen is not, and either are other causes such as intimate partner violence and chronic stress. The aim in this thesis was to investigate the influence of hormones as well as psychological aspects on the most common problems among women seeking care for premenstrual symptoms. In a cross-sectional study, four groups of women were included: ongoing users of oral contraceptives, with or without adverse mood symptoms and previous users, with or without experience of adverse mood. Depression and anxiety were significantly more common in both groups with reported adverse mood, in comparison with their control groups with no adverse mood. Self-reported PMS was significantly more common in those women who reported adverse mood, however, there was no difference in prospectively defined PMS or PMDD between the two groups of previous users. In a RCT with 25 women completing the study, GnRH treatment were tested in combination with two different HRT add-back doses of estradiol, in combination with progesterone and placebo. The higher dose of estrogen 1.5 mg in combination with progesterone induced significantly more pronounced symptoms than in combination with placebo. The lower dose, 0.5 mg gave less symptom recurrence in combination with progesterone. Exposure to violence was investigated among PMDD patients, healthy controls and gynecological patients. Among the participating women, gynecological patients, reported physical and/or emotional abuse significantly more often than did PMDD patients, as well as healthy controls. Chronic stress was investigated with diurnal cortisol, and low-dose dexamethasone test. There was no difference in diurnal secretion of cortisol between PMDD patients and controls. No difference in the degree of dexamethasone suppression was found between PMDD patients and controls. According to the results from these studies, the main symptom provoking factor in women with PMDD appears to be the estradiol and progesterone fluctuations across the menstrual cycle, whereas chronic stress and intimate partner violence appears to be less relevant.
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| 6. |
- Stiernman, Louise, 1994-
(författare)
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Premenstrual dysphoric disorder : brain structure and function, GABAA-active neurosteroids and GABAA receptor plasticity
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Premenstrual dysphoric disorder (PMDD) is an ovarian hormone-bound disorder, characterized by mood symptoms which occur exclusively during the luteal phase of the menstrual cycle. Previous neuroimaging studies of PMDD have primarily reported functional brain differences during the luteal phase in regions of the salience network (SN), which is commonly implicated in mood and anxiety disorders. SN dysfunction may mediate affective and behavioral deficits by leading to enhanced detection and inappropriate assignment of salience to stimuli. What drives altered brain function in PMDD is unknown. However, one influential hypothesis implicates the luteal phase hormone progesterone, and in particular its neurosteroid metabolites. Progesterone-derived neurosteroids increase transmission at the g- aminobutyric acid type A (GABAA) receptor, leading to increased inhibitory tone at the neuronal level. This thesis aimed to i) investigate structural and functional characteristics of the brain in PMDD, ii) relate functional measures to levels of neurosteroids during the luteal phase, and iii) investigate how gene expression of GABAA receptor subunits is altered across the menstrual cycle in PMDD.Results In Study I, we found that women with PMDD had thinner cortices in widespread brain regions, including regions of the SN. In Studies II and III, we found that increases in functional brain measures are most prominent during the symptomatic luteal phase in regions belonging to the SN and in other networks commonly involved in the psychopathology of mood disorders. Furthermore, we could show that increased activity in key nodes of the SN was apparent in the follicular phase and related to the severity of affective symptoms experienced during the luteal phase. Additionally, in Study II, we found that functional activity in the amygdala, a key region of the SN, was differentially associated with serum levels of GABAA receptor- active neurosteroids between PMDD and controls during the luteal phase. Lastly, in Study IV, we found seminal evidence of reduced mRNA expression of the d-GABAA subunit, which imbues GABAA receptors with increased sensitivity to progesterone’s neurosteroid metabolites. Lower expression of d subunits was related to higher amygdala reactivity.Conclusion In this thesis, I provide evidence for altered structure and function in multiple brain networks, particularly the SN in PMDD. Accentuated SN dysfunction during the symptomatic luteal phase may be mediated by the amygdala, and related to abnormal deficits in the expression of neurosteroid-sensitive d- GABAA receptors in response to ovarian hormone fluctuations.
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| 7. |
- Timby, Erika, 1974-
(författare)
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Allopregnanolone effects in women : clinical studies in relation to the menstrual cycle, premenstrual dysphoric disorder and oral contraceptive use
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Premenstrual dysphoric disorder (PMDD) affects 3–8% of women in fertile ages. Combined oral contraceptives (OCs) are widely used and some users experience adverse mood effects. The cyclicity of PMDD symptoms coincides with increased endogenous levels of allopregnanolone after ovulation. Allopregnanolone enhances the effect of γ-aminobutyric acid (GABA) on the GABAA receptor, the principal inhibitory transmitter system in the brain. The sensitivity to other GABAA receptor agonists than allopregnanolone (i.e. benzodiazepines, alcohol and the 5 β epimer to allopregnanolone, pregnanolone) has been reported to depend on menstrual cycle phase and/or PMDD diagnosis. Isoallopregnanolone, the 3 β epimer to allopregnanolone, has previously been used to verify specific allopregnanolone GABAA receptor effects. Saccadic eye velocity (SEV) is a sensitive and objective measurement of GABAA receptor function. Aims: To study the pharmacological effects, and any effect on gonadotropin release, of intravenous allopregnanolone in healthy women. A second aim was to explore whether allopregnanolone sensitivity differs over the menstrual cycle or during OC use in healthy women, and thirdly in PMDD patients. Methods: Ten women were challenged with a cumulative dose of intravenous allopregnanolone in the follicular phase of the menstrual cycle. The effect on FSH and LH was compared to women exposed to isoallopregnanolone. A single dose of allopregnanolone was administered once in the follicular phase and once in the luteal phase in another ten healthy women and in ten PMDD patients, and additionally in ten women using OCs. Repeated measurements of SEV, subjectively rated sedation and serum concentrations after allopregnanolone injections were performed in all studies. Results: Allopregnanolone dose-dependently reduced SEV and increased subjectively rated sedation. Healthy women had a decreased SEV response in the luteal phase compared to the follicular phase. By contrast, PMDD patients had a decreased SEV response and subjectively rated sedation response to allopregnanolone in the follicular phase compared to the luteal phase. There was no difference in the SEV response to allopregnanolone between women using oral contraceptives and healthy naturally cycling women. Allopregnanolone decreased serum levels of FSH and LH whereas isoallopregnanolone did not affect FSH and LH levels. Conclusion: Intravenous allopregnanolone was safely given and produced a sedative response in terms of SEV and subjectively rated sedation in women. The sensitivity to allopregnanolone was associated with menstrual cycle phase, but in the opposite direction in healthy women compared to PMDD patients. The results suggest mechanisms of physiological tolerance to allopregnanolone across the menstrual cycle in healthy women and support that PMDD patients have a disturbed GABAA receptor function. In addition, one of our studies suggests that allopregnanolone might be involved in the mechanism behind hypothalamic amenorrhea.
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| 8. |
- Bixo, Marie, 1957-
(författare)
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Ovarian steroids in rat and human brain : effects of different endocrine states
- 1987
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian steroid hormones are known to produce several different effects in the brain. In addition to their role in gonadotropin release, ovulation and sexual behaviour they also seem to affect mood and emotions, as shown in women with the premenstrual tension syndrome. Some steroids have the ability to affect brain excitability. Estradiol decreases the electroshock threshold while progesterone acts as an anti-convulsant and anaesthetic in both animals and humans. Several earlier studies have shown a specific uptake of several steroids in the animal brain but only a few recent studies have established the presence of steroids in the human brain.In the present studies, the dissections of rat and human brains were carried out macroscopically and areas that are considered to be related to steroid effects were chosen. Steroid concentrations were measured by radioimmunoassay after extraction and separation with celite chromatography. The accuracy and specificity of these methods were estimated.In the animal studies, immature female rats were treated with Pregnant Mare's Serum Gonadotropin (PMSG) to induce simultaneous ovulations. Concentrations of estradiol and progesterone were measured in seven brain areas pre- and postovulatory. The highest concentration of estradiol, pre- and postovulatory, was found in the hypothalamus and differences between the two cycle phases were detected in most brain areas. The preovulatory concentrations of progesterone were low and the highest postovulatory concentration was found in the cerebral cortex.In one study, the rats were injected with pharmacological doses of progesterone to induce "anaesthesia". High uptake of progesterone was found and a regional variation in the formation of 5<*-pregnane-3,20-dione in the brain with the highest ratio in the medulla oblongata.Concentrations of progesterone, 5a-pregnane-3*20-dione, estradiol and testosterone were determined in 17 brain areas of fertile compared to postmenopausal women. All steroids displayed regional differences in brain concentrations. Higher concentrations of estradiol and progesterone were found in the fertile compared to the postmenopausal women.In summary, these studies show that the concentrations of ovarian steroids in the brain are different at different endocrine states in both rats and humans and that there are regional differences in brain steroid distribution.
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