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Background

Mastering emotion regulation is crucial for social skills and mental health. Hormonal fluctuations, particularly in estradiol (E2) levels across the menstrual cycle, significantly impact emotion processing. E2 is known to influence emotion regulation, mental health, and the plasticity of limbic and striatal regions, which are involved in emotion processing and are rich in E2 receptors. Although research indicates that E2 levels may impact gray matter volume (GMV) of limbic and striatal areas, sufficient causal evidence is missing so far. Furthermore, because of the additional fluctuations of progesterone across the menstrual cycle, the sole impact of E2 on brain volume has been difficult to disentangle.

Methods

To isolate the effects of E2 from other fluctuating sex hormones, we used a randomized, placebo-controlled, double-blind, crossover design and administered oral E2 to 27 naturally cycling females during their early follicular phase (low endogenous sex hormone levels). We analyzed emotion regulation strategies and E2 levels to assess their impact on regional GMV.

Results

Our data showed that a rapid increase of E2 was negatively associated with right striatal GMV. Moreover, greater use of reappraisal was associated with reduced GMV of the right striatum. Rapidly increased E2 did not influence GMV of other limbic regions.

Conclusions

These results highlight that rapid increases in E2 and individual differences in emotion regulation dynamically modulate GMV. This offers important implications for female mental and brain health associated with hormonal fluctuations. Considering female endocrine profiles improves hormone-informed health care and therefore supports individualized medicine.

Background: Cardiovascular disease (CVD) risk factors are prevalent in women with polycystic ovary syndrome (PCOS), but prospective data regarding CVD in population-based cohorts are limited.

Aim: This study aims to investigate prospective risk of CVD in Nordic women with PCOS.

Design: This is a national register-based study in women with PCOS and age-matched controls originating from Denmark (PCOS Denmark, N = 27 298, controls, N = 135 019), Finland (PCOS Finland, N = 20 765, controls, N = 59 122), and Sweden (PCOS Sweden, N = 79 454, controls, N = 393 669). The main study outcome was CVD. Cardiovascular disease was defined according to ICD-10 diagnostic codes for major adverse cardiac events, pulmonary embolism, and/or deep venous thrombosis. Cox regression analyses estimated hazard ratio (HR) with 95% CI and adjusted analyses included body mass index (BMI) and education.

Results: The median age at cohort entry was 28 years (Denmark) and 29 years (Finland and Sweden) and the median follow-up time was 8.0-10.0 years. The unadjusted HR (95% CI) for CVD in women with PCOS was 1.30 (1.20; 1.41) in Denmark, 1.45 (1.31; 1.60) in Finland, and 1.52 (1.44; 1.60) in Sweden. Models remained significant after adjusting for obesity and level of education. In a combined meta-analysis including all countries (PCOS, N = 127 517, controls, N = 587 810), the adjusted HR for CVD in women with PCOS was 1.32 (1.25; 1.39). In women with BMI < 25 kg/m² and no type 2 diabetes, the adjusted HR for CVD risk was 1.40 (1.26; 1.55).

Conclusion: The risk of CVD was increased in women with PCOS across the 3 Nordic countries, also among women with BMI < 25 kg/m².

Testosterone and oestrogens play significant roles in female physiology, extending beyond reproductive functions to influence brain health, mood regulation, and behaviour. Testosterone low-dose therapy is increasingly considered for alleviating sexual dysfunction symptoms in postmenopausal women, and has been recently investigated as therapy for depressive symptoms, though the mechanisms and safety of this approach are not entirely clear. Specifically, the effects of testosterone use on brain oestrogen synthase (aromatase), which maintains the balance between androgens and oestrogens, remain unexplored. This study investigated the effects of short-term, low-dose testosterone administration on brain oestrogen synthase availability and associated mood and behavioural changes in healthy women. Healthy women were exposed to 1 week of low-dose testosterone (10 mg/day). Binding of oestrogen synthase was examined by [¹¹C]cetrozole positron emission tomography before and during testosterone exposure. Psychometric assessment of depression, anxiety, and aggression was performed at the same time. Peripheral testosterone levels were significantly increased (up to 33-fold) upon treatment, which had no significant effect on brain oestrogen synthase binding in the thalamus, as supported by Bayesian analyses, nor in the hypothalamus and amygdala. Psychometric measures of depression, anxiety, and aggression also remained unchanged by testosterone treatment. These findings suggest that short-term, clinically relevant testosterone administration has no major effects on the brain oestrogen synthase availability in healthy women, which may reassure patients with hypoactive sexual desire disorder considering this treatment. Larger, long-term studies are needed to confirm these results and explore effects in patients with clinical need for testosterone treatment.

Purpose

Premenstrual dysphoric disorder (PMDD) has been associated with altered grey matter architecture in a trait-like manner. Personality traits, shaped largely by genetics and linked to depressive disorders, may relate to structural properties of the brain and could represent a potential factor mediating vulnerability for PMDD. However, these possible associations remain largely unexplored.

Methods

The present study assessed personality traits in participants with PMDD and healthy controls, as well as how per-sonality is related to symptom severity and cortical surface measures in PMDD. Healthy controls and patients completed the Swedish Universities Scale of Personality. Following prospective validation of the PMDD diagnosis, patients had their brain scanned with magnetic resonance imaging (MRI) during the symptomatic luteal phase of the menstrual cycle. Personality of controls and patients was compared using Mann-Whitney U tests. Associations of personality with symptom severity and brain surface parameters were tested through correlation analysis.

Results

PMDD was associated with higher scores in neuroticism and aggressiveness. Aggressiveness was positively cor-related with the severity of irritability/anger, though not significant after correcting for multiple testing. Regarding cortical structural measures, aggressiveness was negatively correlated with cortical complexity of the parahippocampal gyrus.

Conclusion

Considering neuroticism and aggressiveness during screening for PMDD could contribute to the identification of risk factors and personalized treatment of females suffering from PMDD

Background: There is a great need for non-estrogenic treatment of vulvovaginal atrophy (VVA) symptoms affecting sexual function and quality of life. Women with breast cancer on anti-estrogenic therapy are particularly vulnerable and in need of help. The primary aim of this proof-of-concept trial was to evaluate the efficacy of vaginal tamoxifen in reducing the most troublesome VVA symptom.

Methods: In this randomized, double blind, placebo-controlled study, 115 postmenopausal women, with or without breast cancer, were randomized to 20 mg vaginal tamoxifen once weekly or placebo (1:1). Follow-up after one and three-months of treatment, included self-reported VVA symptoms on the Endocrine Symptom Subscale of FACT-B, and gynecologic exams for VVA score and measurement of vaginal pH and endometrial thickness.

Findings: After three months, 37 (68.6 %) of women on vaginal tamoxifen reported their most troublesome VVA symptom to be mild or not present at all, whereas corresponding number in the placebo group was 5 (9.1 %), p < 0.001. Expressed as odds, women on vaginal tamoxifen were more likely to report no or minor symptoms after three-months, OR 21.76 (95 % CI 7.36 - 64.3). The improvement in self-reported outcomes was accompanied by improvements in VVA scores and vaginal pH, p <0.001.

Interpretation: This study has demonstrated that more than two-thirds of the women on vaginal tamoxifen improved in their most troublesome VVA symptom. This is likely due to a tamoxifen-induced estrogen agonistic effects in vagina in a low-estrogen environment. While findings are promising, further studies on improved vaginal administration and endometrial safety concerns are needed.

The transition to menopause is marked by a gradual decrease of estradiol. At the same time, the risk of dementia increases around menopause and it stands to reason that estradiol (or the lack thereof) plays a significant role for the development of dementia and other age-related neuropathologies. Here we investigated if there is a link between brain aging and estradiol-associated events, such as menarche and menopause. For this purpose, we applied a well-validated machine learning approach in a sample of 1,006 postmenopausal women who were scanned twice approximately two years apart. We observed less brain aging in women with an earlier menarche, a later menopause, and a longer reproductive span (i.e., the time interval between menarche and menopause). These effects were evident both cross-sectionally and longitudinally, which supports the notion that estradiol might contribute to brain preservation. However, more research is required as effects were small and no direct measures of estradiol were obtained in the current study.

Objectives: Premenstrual dysphoric disorder (PMDD) is a hormone-related condition affecting women in childbearing age, which has been only quite recently recognized as a depressive disorder. PMDD is characterized by affective and physical symptoms that peak in the luteal phase of the menstrual cycle, and remit shortly in the beginning of the next cycle. SSRIs administered during the symptomatic phase represent the gold-standard treatment for women with PMDD, due to their rapid and efficacious action. The key symptoms of PMDD (depressed mood, anxiety, irritability, emotional lability) suggest an impaired top-down inhibitory process involving limbic structures. However, the neural correlates of SSRI treatment in PMDD remain unexplored. We aimed at investigating the effect of intermittent SSRI treatment on the brain in PMDD, by use of functional MRI.

Methods: This pharmaco-MRI study consisted in a double-blind, randomized, placebo-controlled trial in which 62 women with PMDD were treated with either 20mg/day escitalopram or placebo, during their luteal phase. Brain reactivity during the Point Subtraction Aggression Paradigm was assessed after treatment, in relation to aggression-related stimuli.

Results: Intermittent escitalopram treatment significantly reduced PMDD symptoms compared to placebo, particularly irritability. Aggressiveness diminished as an effect of treatment, with irritability mediating the effect. Reactivity to provocations was associated with lower activation of the anterior insula upon treatment with escitalopram, which also positively related to irritability levels.

Conclusions: These findings suggest a potential neural mechanism underlying the therapeutic effects of SSRIs in PMDD and provide insights into their role in modulating reactive aggression.

Fetal macrosomia is associated with adverse short- and long-term outcomes for the mother and the child. Present models to predict fetal macrosomia cannot be used in all settings, and their precision could be improved. We assessed if waist circumference could replace or outperform weight for early pregnancy prediction of macrosomia. We included 5827 women in this population-based cohort study and assessed the influence of early pregnancy waist circumference and weight on the prediction of macrosomia with logistic regression analysis. We generated receiver operating characteristic (ROC) curves and calculated the area under the curve (AUC) to compare models, including waist circumference, weight, or neither of them. The odds of macrosomia increased with a larger waist circumference (adjusted odds ratio (AOR) 1.03 (95% Confidence Interval (CI) 1.02, 1.04)). For women with waist circumference between 80 and 88 cm the AOR was 1.41 (95% CI 1.09, 1.82) and women with waist circumference ≥ 88 cm had AOR 1.98 (95% CI 1.56, 2.53) for macrosomia. There was no difference in predictive capacity between waist circumference and weight in the macrosomia prediction model. The AUC was 0.75 (95% CI 0.72, 0.77) for waist circumference and 0.74 (95% CI 0.72, 0.77) for weight. The model that excluded waist circumference and weight had an AUC of 0.72 (95% CI 0.70, 0.75). The predictive capacity of the model including waist circumference was, however, higher than that of the model without waist circumference or weight (p < 0.001). In conclusion, waist circumference can replace weight in an early pregnancy macrosomia prediction model.