Umeå University's logo

Background: Emotion regulation deficits have been highlighted as a transdiagnostic feature of multiple psychiatric disorders, including premenstrual dysphoric disorder (PMDD). In this study, we hypothesized that deficient prefrontal top-down regulation of key nodes of the salience network (SN) is a characteristic of PMDD, driven by increased levels of progesterone-derived neuroactive steroids.

Methods: Functional magnetic resonance imaging was used to investigate menstrual cycle–related variations in brain activity and connectivity during 2 emotional tasks (emotion generation and regulation) in 29 women with PMDD and 27 control women. We also examined whether differential brain activation between groups was related to serum levels of progesterone-derived neuroactive steroids and premenstrual symptom severity.

Results: Women with PMDD showed increased reactivity in key nodes of the SN and, at subthreshold level, in the default mode network during the luteal phase when passively viewing negative emotional stimuli. Intriguingly, SN hyperactivity in patients with PMDD was also apparent during the follicular phase and related to premenstrual symptom severity. Women with PMDD and control women had similar network connectivity patterns and activity in regions associated with the conscious control of emotion in PMDD. No link to progesterone-derived neuroactive steroids was found.

Conclusions: Multiple network aberrations during the luteal phase may explain the development of mood symptoms during the luteal phase. Furthermore, higher baseline (follicular) SN activity may render women with PMDD more susceptible to severe mood symptoms in response to hormonal fluctuations. What drives increased SN activity in the follicular phase is unknown, but innate and neuroplastic mechanisms have been proposed.

Problem: Various chemokines have been linked to endometriosis. Notably, chemokines such as CCL2, CXCL8, and CXCL1 have also been shown to promote nociception. In this study, we investigated whether increased serum concentrations and endometrial expression of chemokines (specifically CCL2, CXCL8, and CXCL1) are associated with heightened severity of pain symptoms in women with endometriosis.

Method of Study: The study included women with endometriosis (with [n = 27] and without [n = 24] hormonal treatment) as well as healthy controls (n = 22). All participants underwent blood sampling and an endometrial biopsy during the secretory phase of the menstrual cycle. Symptom severity in the patient group was assessed using the pain dimension of the Endometriosis Health Profile 30 (EHP-30) and a visual analog scale (VAS) for pain.

Results: Serum levels of CCL2 and CXCL1, as well as endometrial expression of CXCL8, were lower in women with endometriosis compared to controls. Furthermore, increased serum levels of CCL2, CXCL8, and CXCL1 were associated with higher EHP-30 pain domain scores in women with endometriosis. Similarly, elevated endometrial expression of CXCL8 and CXCL1 correlated with higher VAS scores. Notably, when the patient group was stratified based on ongoing hormonal treatment, CXCL1 emerged as the most promising target, with both increased serum concentration and endometrial expression consistently being associated with greater symptom severity.

Conclusions: Our results suggest that chemokines, particularly CXCL1, are associated with greater pain severity and reduced quality of life in women with endometriosis. However, these correlations do not establish causality and should be interpreted with caution.

Objective: The mechanisms behind endometriosis-related pain are not yet fully understood. To determine if there is a difference in the density of endometrial nerve fibers between women with endometriosis and healthy controls, and to explore how the density of these nerve fibers and hormone levels correlate with the severity of symptoms experienced by the women.

Study Design: In this case-control study, 76 women with endometriosis and 24 healthy controls were included. The patient group was divided into two subgroups: those with and without hormonal treatments. Endometrial biopsies were taken and stained to detect PGP 9.5, a nerve fiber marker. Blood samples were collected for hormone analysis. Pain symptom severity was measured using VAS and EHP30.

Results: Women with endometriosis had a higher density of endometrial nerve fibers than healthy controls (median [range]: 2.0 [2.0–4.0] vs. 1.0 [0.0–1.0] fibers/mm², P < 0.001). This increased density was associated with more severe pain (β = 0.130 [95 % CI: 0.019, 0.240], P = 0.02). Women with endometriosis, regardless of hormone treatment, had a higher density of endometrial nerve fibers (3.0 [2.0–4.0] and 2.0 [1.0–4.0] fibers/mm², respectively) compared with healthy controls (1.0 [0.0-u1.0] fibers/mm², both P < 0.001). The density was not significantly different between those receiving and not receiving hormone treatment. The allopregnanolone/progesterone ratio was greater in women with endometriosis not receiving hormone treatment (0.002 [0.001–0.004]) than in healthy controls (0.001 [0.000–0.005]) and women receiving hormone treatment (0.001 [0.000–0.006], P = 0.02 and 0.001, respectively). A greater allopregnanolone/progesterone ratio was associated with more severe pain (β = 20.662 [95 % CI: 0.202, 41.121], P = 0.048), but hormone levels (estrogen, progesterone, and allopregnanolone) were not associated with endometrial nerve fiber density.

Conclusion: Women with endometriosis have a higher nerve fiber density in the endometrium, linked to more severe pain, regardless of hormone treatment. Increased progesterone metabolism to allopregnanolone may be a target for managing endometriosis pain.

Objectives: SLE and SSc are more common in women, partly due to differences in female sex hormones. Menopausal hormone therapy (MHT) is widely used to alleviate climacteric symptoms. Here, the relationship between MHT and SLE/SSc was investigated in a nested case-control study.

Methods: Women with SLE or SSc and controls, matched 1 up to 10 on sex, birth year and region, from the general population of Sweden. Data on exposures and potential confounders were obtained from the National Patient and Prescribed Drug Register as well as the Longitudinal Integration Database for Health Insurance and Labour Market Studies. Exposure was defined as the dispensation of any MHT medication prior to the diagnosis/matching. The association between MHT and SLE/SSc, and whether the strength of the association, expressed as odds ratios (OR) and 95% CI, varied by type, route of administration, and duration of use, was assessed using conditional logistic regression, adjusted for education, income and sick leave.

Results: In total, 943 women with SLE and 733 women with SSc were identified between 2009 and 2019. We detected a significant association between MHT use and risk of SLE (OR = 1.3; 95% CI: 1.1–1.6), and SSc (OR = 1.4; 95% CI: 1.2–1.7). Women who had both systemic and local MHT medications dispensed exhibited the highest risk of SLE (OR = 1.9; 95% CI: 1.4–2.7) and SSc (OR = 1.8; 95% CI: 1.2–2.5).

Conclusion: These findings indicate an association between MHT and SLE/SSc, independent of socioeconomic factors, warranting further investigation into the role of exogenous female sex hormones in SLE/SSc pathogenesis.

Background Premenstrual dysphoric disorder (PMDD) is common, with at least 3% of the female population affected by one or more of the typical mood symptoms of depression, irritability, mood swings and anxiety. The cyclicity and close relationship to the luteal phase of the menstrual cycle is characteristic for this syndrome and positive allosteric modulators (PAMs) on the GABAA receptor, especially allopregnanolone, are believed to be involved in the symptomatology.

Aim To summarise the research on the role of PAMs and other neuroactive steroids in the pathophysiology of PMDD.

Method PubMed was searched for articles including the terms Premenstrual syndrome, AND neurosteroids OR allopregnanolone OR GABA OR oestradiol. Many additional publications were previously known to the authors and basic animal research was covered in a secondary step through reference lists.

Results There is evidence that allopregnanolone, like other PAMs of the GABAA receptor, is sedative in high concentrations and, in a minor proportion of the population, causes anxiety and irritability at lower levels, pointing to an inter-individual difference in sensitivity. In research comparing women with PMDD and healthy controls, differences in brain function and subcomposition of GABAA receptors related to levels of allopregnanolone have been found. Also, the varying levels of neuroactive steroids in general seem to worsen the symptoms. Supressed ovulation is effective but add-back hormones are necessary to prevent severe side-effects and could cause adverse mood in these individuals.

Conclusions There is yet no effective treatment for PMDD available. Allopregnanolone seems to be a key provocateur of PMDD symptoms in susceptible individuals. Future research should focus on interventions that interfere with the effects of neurosteroids or the plasticity of the GABAA receptor itself.

Progesterone is a highly lipophilic gonadal hormone that can influence behavior and mental health through its receptors in the brain. Fluctuations in progesterone levels across critical periods of a females life are associated with increased susceptibility to mental conditions. This review highlights the effects of progestagens, including progesterone and synthetic progestins, on the brain, mood, stress, and cognition in females. The primary focus is on experimental pharmacological research that teases out the distinct effects of progestagens from those of estrogens. Additionally, the key literature on puberty, the menstrual cycle, pregnancy, perimenopause, hormonal contraceptives, and menopausal hormone therapy is reviewed, although conclusions are limited by the nested effects of progestagens and estrogens. Single study-findings suggest an influence of progesterone on amygdala reactivity related to processing of emotional stimuli and memory. In patients with premenstrual dysphoric disorder, progesterone receptor modulation improves premenstrual mood symptoms and potentially enhances fronto-cingulate control over emotion processing. The interaction between progestagens and the systems involved in the regulation of stress seems to influence subjective experiences of mood and stress. Sparse studies investigating the effects of progestin-only contraceptives suggest effects of progestagens on the brain, mood, and stress. Progesterone and progestins used for contraception can influence neural processes as myelination and neuroprotection, exerting protective effects against stroke. Concerning menopausal hormonal therapy, the effects of progestins are largely unknown. Levels of progesterone as well as type, administration route, timing, dose regimen, metabolism, and intracellular activity of progestins in hormonal contraceptives and menopausal hormonal therapy are factors whose effects remain to be elucidated. Altogether, current knowledge highlights the potential role of progestagens in females health but also calls for well-designed pharmaco-behavioral studies disentangling the effects of progestagens from those of estrogens.

Background: Premenstrual dysphoric disorder (PMDD) is characterized by symptoms of irritability, affective lability, anxiety, and depression, which occur only in the luteal phase of ovulatory menstrual cycles. This offers an ideal model to assess the neural correlates of the on and off switch of mood symptoms. Recently, we highlighted differences in grey matter volume between individuals with PMDD and healthy controls during the luteal phase, depicting smaller volumes in those diagnosed with the condition. However, it is unknown whether such alterations represent state-like changes specific to the symptomatic phase, or trait-like characteristics.

Methods: Here, 28 patients with PMDD and 26 controls underwent anatomical magnetic resonance imaging during the mid-follicular and the late-luteal phases of the menstrual cycle. For each time point, we assessed grey matter volumes over the whole brain using voxel-based morphometry.

Results: We found no group-by-phase interaction effect on grey matter volumes, but a main effect of group across menstrual cycle phases, suggesting trait rather than state structural markers of PMDD. Patients displayed smaller volumes compared to controls, primarily in the cerebellum and cuneus, and at a trend-level in ventral occipito-temporal, parietal, paracentral and orbitofrontal areas, as well as the putamen (Cohen’s d range: 0.4–1.1).

Conclusions: These findings suggest that the differences in grey matter volumes found in PMDD are stable across the menstrual cycle and could represent trait-like, vulnerability markers of PMDD.

Premenstrual dysphoric disorder (PMDD) has been hypothesized to be related to an altered sensitivity of the γ-aminobutyric acid type A (GABAA) receptor to progesterone-derived neurosteroids. GABAA receptor sensitivity to neurosteroid-modulation is dependent on its subunit composition. In the present study, we used quantitative reverse transcription polymerase chain reactions (RT-qPCR) to compare messenger ribonucleic acid (mRNA) expression of GABAA receptor subunits in peripheral mononuclear cells (PBMCs) across the menstrual cycle in 29 women with PMDD and 27 controls. We related mRNA subunit expression to serum levels of neurosteroids and to functional activation of the amygdala, a key brain region involved in emotion generation, measured using functional magnetic resonance imaging (fMRI). Women with PMDD had lower mRNA expression of the delta GABAA receptor subunit during the symptomatic, luteal phase (compared to the asymptomatic, follicular phase) of the menstrual cycle. Lower delta mRNA expression was related to higher amygdala activation in PMDD women. GABAA receptors incorporating the delta subunit are especially sensitive to neurosteroid modulation. It is possible that the mood symptoms of PMDD are mediated by an inability to effectively adjust the expression of this receptor type in response to neurosteroid fluctuations, leading to dysregulation GABAergic tone and increased activity in emotion-generating brain circuits.

Background: Premenstrual dysphoric disorder (PMDD) is an understudied, debilitating, and hormone-related mental disorder. Recent evidence suggests alterations in white matter structure during the symptomatic luteal phase in PMDD. In this study, white matter volumes (WMVs) in the brains of women with PMDD versus control women were compared across the menstrual cycle, to determine whether these differences reflect state- or trait-like characteristics.

Methods: Anatomical magnetic resonance imaging was performed during the midfollicular phase and the late luteal phase of the menstrual cycle in 28 women with PMDD and 27 control women. WMVs were assessed using voxel-based morphometry, employing both region-of-interest (ROI) and exploratory whole-brain approaches.

Results: No group-by-phase interaction effects on WMVs were found. Across menstrual cycle phases, women with PMDD exhibited greater WMVs than control women within ROIs (in the bilateral uncinate fasciculus, right inferior fronto-occipital fasciculus, and left crus and fimbria of the fornix) and across the whole brain (in inferior occipital areas and near the angular gyrus), indicating trait- rather than state-like structural markers of PMDD.

Conclusions: These findings suggest that women with PMDD exhibit larger WMVs than healthy control women, during both the symptomatic and asymptomatic phases of the menstrual cycle, in white matter tracts involved in emotion processing and regulation, memory, and connecting limbic and prefrontal regions of relevance to mood disorders.