Many women self-report discomfort, depression, mood changes, and irritability in conjunction with menstruation which has been termed Premenstrual Syndrome (PMS). Prior to the creation of the disease/disorder category PMS, disorders with similar symptoms like “hysteria” and “involutional melancholia” were ascribed to women reporting those types of complaints. These diagnoses were based on archaic claims about women’s anatomy and behavior. Modern medical researchers contend that women’s complaints have a physiological basis, yet they cannot definitively tie PMS to any specific physiological etiological pathway, either hormonal or neurological. This thesis explores the argument that the social norms for women’s roles and their associated behaviors are related to the appearance of a disease/disorder category named PMS in the United Kingdom and the United States. Many of women’s complaints may instead be symptoms of social problems (with social remedies) related to role conflict or role strain.

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.

Bakgrund: Cirka 75% av alla fertila kvinnor påverkas i varierande grad av premenstruella symtom. 15–20% har uttalad PMS medan 2–5% drabbas av den allvarligare varianten PMDS. De vanligaste symtomen är ilska, irritabilitet, ångest, ökad svullnadskänsla i kroppen, ömhet i brösten, huvudvärk, led-/muskelvärk och viktökning. Syfte: Syftet med litteraturstudien var att undersöka kvinnors erfarenheter av att leva med PMS och PMDS. Metod: Examensarbetet utfördes som en litteraturstudie med kvalitativ studiedesign där tio vetenskapliga artiklar sammanställdes för att kunna svara på det valda syftet. Resultat: För vissa kvinnor innebar premenstruella besvär år av månatligt lidande, för andra var det ett tecken på att vara en frisk kvinna. Kvinnorna hade olika copingstrategier för att få vardagen att fungera, de vanligaste var egen tid och att praktisera självövervakning. Många upplevde en negativ samhällelig bild av PMS och hur den premenstruella kvinnan uppfattades, dessa normer och ideal påvisades ha en skadlig inverkan på den egen självbilden och hur kvinnorna upplevde sina premenstruella besvär. Jean Watson (1985) belyser vikten av att sjuksköterskan ingjuter tro och hopp i patienten inför den situation den befinner sig i. På så vis kan sjuksköterskan bidra till beteende- och attitydförändringar. Slutsats: Kvinnorna upplever en samhällelig okunskap om PMS och PMDS som påverkar i vilken utsträckning de vågar tala om sina besvär. Okunskapen leder till att kvinnorna inte får det stöd och den hjälp de behöver för att klara vardagen, något som har direkt inverkan på livskvaliteten. Ökad medvetenhet och kunskap hos sjuksköterskan är grundläggande för att kunna ge adekvat och personcentrerad vård till dessa kvinnor. / Background: Approximately 75% of all women of childbearing age are affected by premenstrual symptoms. 15–20% have more distinct PMS, while 2–5% suffer from the more severe version PMDD. The most common symptoms are anger, irritability, anxiety, increased bloating, soreness in the breasts, headaches, joint/muscle pain and weight gain. Aim: The aim of the literature study was to investigate women's experiences of living with PMS and PMDD. Method: The thesis was carried out as a literature study with a qualitative study design. Ten scientific articles were compiled in order to answer the aim of the study. Results: For some women, PMS can mean years of monthly suffering, for others it's a sign of being a healthy woman. Women witnessed having to resort to different coping strategies to make everyday life work, the most common were personal time and self-monitoring. Many women experienced a negative societal image of PMS and how the premenstrual woman was perceived, these norms and ideals have been shown to have a harmful impact on their self-image and how they experience their premenstrual distress. Jean Watson (1985) highlights the importance of the nurse instilling faith and hope in the patient before the situation they find themselves in. In this way, the nurse can contribute to behavioral and attitudinal changes. Conclusion: Women feel that there is a societal ignorance that affects the extent to which they are comfortable speaking about their distress. This means that women do not receive the support and help they need to cope with everyday life, something that has a direct impact on their quality of life. Increased awareness and knowledge is fundamental in order for the nurse to provide adequate and person centered care for these women.

There are robust sex differences in brain anatomy, function, as well as neuropsychiatric and neurodegenerative disease risk (1-6), with women approximately twice as likely to suffer from a depressive illness as well as Alzheimer’s Disease. Disruptions in ovarian hormones likely play a role in such disproportionate disease prevalence, given that ovarian hormones serve as key regulators of brain functional and structural plasticity and undergo major fluctuations across the female lifespan (7-9). From a clinical perspective, there is a wellreported increase in depression susceptibility and initial evidence for cognitive impairment or decline during hormonal transition states, such as the postpartum period and perimenopause (9-14). What remains unknown, however, is the underlying mechanism of how fluctuations in ovarian hormones interact with other biological factors to influence brain structure, function, and chemistry. While this line of research has translational relevance for over half the population, neuroscience is notably guilty of female participant exclusion in research studies, with the male brain implicitly treated as the default model and only a minority of basic and clinical neuroscience studies including a female sample (15-18). Female underrepresentation in neuroscience directly limits opportunities for basic scientific discovery; and without basic knowledge of the biological underpinnings of sex differences, we cannot address critical sexdriven differences in pathology. Thus, my doctoral thesis aims to deliberately investigate the influence of sex and ovarian hormones on brain states in health as well as in vulnerability to depression and cognitive impairment:Table of Contents List of Abbreviations ..................................................................................................................... i List of Figures .............................................................................................................................. ii Acknowledgements .....................................................................................................................iii 1 INTRODUCTION .....................................................................................................................1 1.1 Lifespan approach: Sex, hormones, and metabolic risk factors for cognitive health .......3 1.2 Reproductive years: Healthy models of ovarian hormones, serotonin, and the brain ......4 1.2.1 Ovarian hormones and brain structure across the menstrual cycle ........................4 1.2.2 Serotonergic modulation and brain function in oral contraceptive users .................6 1.3 Neuropsychiatric risk models: Reproductive subtypes of depression ...............................8 1.3.1 Hormonal transition states and brain chemistry measured by PET imaging ...........8 1.3.2 Serotonin transporter binding across the menstrual cycle in PMDD patients .......10 2 PUBLICATIONS ....................................................................................................................12 2.1 Publication 1: Association of estradiol and visceral fat with structural brain networks and memory performance in adults .................................................................................13 2.2 Publication 2: Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations ..............................................28 2.3 Publication 3: One-week escitalopram intake alters the excitation-inhibition balance in the healthy female brain ...............................................................................................51 2.4 Publication 4: Using positron emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression ..........65 2.5 Publication 5: Increase in serotonin transporter binding across the menstrual cycle in patients with premenstrual dysphoric disorder: a case-control longitudinal neuro- receptor ligand PET imaging study ..................................................................................82 3 SUMMARY ...........................................................................................................................100 References ..............................................................................................................................107 Supplementary Publications ...................................................................................................114 Author Contributions to Publication 1 .....................................................................................184 Author Contributions to Publication 2 .....................................................................................186 Author Contributions to Publication 3 .....................................................................................188 Author Contributions to Publication 4 .....................................................................................190 Author Contributions to Publication 5 .....................................................................................191 Declaration of Authenticity ......................................................................................................193 Curriculum Vitae ......................................................................................................................194 List of Publications ................................................................................................................195 List of Talks and Posters ......................................................................................................196

Introdução: O diagnóstico da Síndrome Pré-menstrual (SPM) é um desafio. O uso de questionários estruturados está bem estabelecido, e a ferramenta mais aceita é o DRSP, um questionário prospectivo auto preenchido por ao menos dois meses. O PSST é um questionário retrospectivo de autoaplicação, preenchido em um único momento. Objetivo: comparar estes dois instrumentos (PSST e DRSP) para o diagnóstico da SPM. Método: Um estudo transversal com 127 mulheres entre 20 a 45 anos com queixas de SPM. As mulheres foram avaliadas quanto ao peso, altura, Índice de Massa Corporal (IMC). Após exclusão de casos de depressão através do Prime-MD, as pacientes completaram o PSST e foram orientadas a preencherem o DRSP durante dois meses. A concordância entre os dois questionários foi avaliado pelo cálculo de Kappa (k) e valores do coeficiente PABAK. Resultados: Do total de mulheres que atenderam ao chamado, 282 (74%) preencheram os critérios de elegibilidade e responderam o PSST. Entre estas 282 mulheres, somente 127 (45%) completaram o questionário diário (DRSP) por dois ciclos. O percentual das mulheres com diagnóstico de SPM através do DRSP foi de 74,8%, e pelo PSST foi 41,7%. O percentual das mulheres com diagnóstico de TDPM pelo DRSP foi de 3,9%, e pelo PSST foi de 34,6%. Assim, verificou-se uma maior prevalência de SPM com o DRSP do que com o PSST. De outra parte a TDPM foi mais dignosticada pelo PSST do que com o DRSP. O número de pacientes consideradas “normais” foi semelhante com os dois instrumentos. Na avaliação entre os dois instrumentos verificou-se não haver nenhuma concordância (Kappa = 0,12) nos resultados do diagnóstico de SPM e TDPM (Coeficiente Pabak resultou = 0,39). Para a trigem de SPM/TDPM o PSST tem uma sensibilidade de 79% e especificidade de 33,3%. Conclusão: O PSST deve ser considerado como uma ferramenta de triagem diagnóstica. Conclui-se que os casos SPM/TDPM do PSST devem ser sempre melhor avaliados pelo DRSP. / Background: The diagnosis of Premenstrual Syndrome (PMS) is a challenge. The use of structured questionnaires is well established and the most accepted is the DRSP, a prospectively self-administered questionnaire that needs two months at least to be completed. The PSST is a retrospective self-scale questionnaire, filled at a single time. Aim: To compare these two instruments (PSST and DRSP) to diagnosis PMS. Methods: A cross-sectional study with 127 women between 20 and 45 years with PMS complaints. The women were evaluated about weight, high, Body Mass Index (BMI). After the exclusion of depression by the Prime-MD Questionnaire, the PSST was completed and the women were oriented to complete the DRSP for two months. The agreement between the two questionnaires was assessed by calculating the Kappa (k) and PABAK values. Results: 282 (74% of all the women) women met eligibility criteria and answered the PSST. Only 127 (45% of the 282 women) completed the daily questionnaire (DRSP) for two cycles. The percentual of women with PMS diagnosis by the DRSP was 74.8%, and by PSST was 41.7%. The percentual of women with PMDD diagnosis by the DRSP was 3.9%, and by the PSST was 34.6%. The number of patients considered “normal” (with the symptoms above the necessary for the diagnostic the PMS) was similar with both questionnaires. We found no agreement between the two instruments (Kappa = 0.12) in the diagnosis of PMS and PMDD (Pabak coefficient keep this result = 0.39). For screening PMS/PMDD the PSST has a sensitivity of 79% and a specificity 33.3%. Conclusion: The PSST should be considered as diagnostic screening tool. We concluded that positive PMD/PMDD cases of PSST should be ever better evaluated by DRSP.

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.

Background: A recent epidemiological analysis on premenstrual dysphoric disorder (PMDD) in the community revealed increased rates of DSM-IV posttraumatic stress disorder (PTSD) among women suffering from PMDD. Aims: To explore whether this association is artifactual or might have important pathogenic implications. Methods: Data come from a prospective, longitudinal community survey of an original sample of N¼1488 women aged 14–24, who were followed-up over a period of 40 to 52 months. Diagnostic assessments are based on the Composite International Diagnostic Interview (CIDI) using the 12-month PMDD diagnostic module. Data were analyzed using logistic regressions (odds ratios) and a case-by-case review. Results: The age adjusted odds ratio between PTSD and threshold PMDD was 11.7 (3.0–46.2) at baseline. 10 women with full PTSD and at least subthreshold PMDD were identified at follow-up. Most reported an experience of abuse in childhood before the onset of PMDD. Some had experienced a life-threatening experience caused by physical attacks, or had witnessed traumatic events experienced by others. 3 women reported more than one traumatic event. Conclusions: A case-by-case review and logistic regression analyses suggest that women with traumatic events and PTSD have an increased risk for secondary PMDD. These observations call for more in-depth analyses in future research.

It is known that some psychiatric disorders may deteriorate in relation to the menstrual cycle. However, in some conditions, such as premenstrual dysphoric disorder (PMDD), symptomatology is triggered mainly by the variations in ovarian steroid hormones. Although symptoms induced by fluctuations in ovarian steroids often are affective, little is known about how emotion processing in women is influenced by variations, or actual levels, of ovarian steroid hormones. The general aim of this thesis was to evaluate menstrual cycle effects on reactivity in emotion generating and controlling areas in the corticolimbic system to emotional stimulation and anticipation, in healthy controls and women with PMDD. A second aim was to evaluate corticolimbic reactivity during long-term administration of exogenous ovarian steroids. In study I, III and IV effects of the menstrual cycle on emotional reactivity in women with PMDD was studied. In study I, women with PMDD in displayed higher amygdala reactivity than healthy controls to emotional faces, not in the luteal phase as was hypothesised, but in the follicular phase. No difference between menstrual cycle phases was obtained in women with PMDD, while healthy controls had an increased reactivity in the luteal phase. The results of study I was further elaborated in study III, where women with PMDD were observed to have an increased anticipatory reactivity to negative emotional stimuli. However, no differences in amygdala reactivity to emotional stimuli were obtained across the menstrual cycle. Finally, in study IV the hypothesis that amygdala reactivity increase in the luteal phase in women with PMDD is linked to social stimuli rather than generally arousing stimuli was suggested, tested and supported. In study II, re-exposure to COC induced mood symptoms de novo in women with a previous history of COC-induced adverse mood. Women treated with COC reported increased levels of mood symptoms both as compared to before treatment, and as compared to the placebo group. There was a relatively strong correlation between depressive scores before and during treatment. The effects of repeated COC administration on subjective measures and brain function were however dissociated with increased aversive experiences accompanied by reduced reactivity in the insular cortex.

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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