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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.

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.

Neuroactive steroids including allopregnanolone are implicated in the pathophysiology of peripartum depressive symptoms (PDS). We performed a systematic review searching PubMed/Embase/PsychInfo/Cinhail through 08/2023 (updated in 07/2024), and conducted a random-effects meta-analysis of studies comparing allopregnanolone blood concentrations in women with versus without PDS at various timepoints during the 2(nd) and 3(rd )trimester and the postpartum period, calculating standardized mean differences (SMDs) and 95% confidence intervals (CIs). Meta-regression and subgroup analyses included age, diagnoses of affective disorders before pregnancy, antidepressant treatment, analytical methods, and sample type. Study quality was assessed using the Newcastle-Ottawa-scale. The study protocol was registered on PROSPERO (registration number CRD42022354495). We retrieved 13 studies with 2509 women (n = 849 with PDS). Allopregnanolone concentrations did not differ between women with versus without PDS at any timepoint (p > 0.05). Allopregnanolone concentrations assessed during pregnancy did not differ for women with versus without PDS at postpartum follow-up (p > 0.05). Subgroup analyses indicated higher allopregnanolone concentrations in women with versus without PDS at gestational weeks 21-24 and 25-28 (SMD = 1.07, 95% CI = 0.04, 2.11 and SMD = 0.92, 95% CI = 0.26, 1.59 respectively). Moreover, we reported differences between studies using mass-spectrometry combined with chromatography versus immunoassays at gestational weeks 25-28 (p = 0.01) and plasma versus serum samples at gestational weeks 21-24 (p = 0.005). Study quality was rated as poor, good, and fair for two, one and ten studies respectively. PDS were not associated with differences for allopregnanolone concentrations. The use of heterogenous peripartum time points, study cohorts, depression symptom measures and analytical methods has hampered progress in elucidating neuroactive steroid signaling linked to PDS.

Introduction: It is well known that both women with polycystic ovary syndrome (PCOS) and women with gestational diabetes mellitus (GDM) have increased risks of adverse pregnancy outcomes, but little is known whether the combination of these two conditions exacerbate the risk estimates. We explored risk estimates for adverse pregnancy outcomes in women with either PCOS or GDM and the combination of both PCOS and GDM.

Material and methods: Retrospective nationwide register-based cohort study in Sweden including women who gave birth to singleton infants during 1997–2015 (N=281 806).The risk of adverse pregnancy outcomes were estimated for women exposed for PCOS-only (n = 40 272), GDM-only (n = 2236), both PCOS and GDM (n = 1036) using multivariate logistic regression analyses. Risks were expressed as odds ratios with 95% confidence intervals (CIs) and adjusted for maternal characteristics, including maternal BMI. Women with neither PCOS nor GDM served as control group.

Main Outcome Measures: Maternal outcomes were gestational hypertension, preeclampsia, postpartum haemorrhage, and obstetric anal sphincter injury. Neonatal outcomes were preterm birth, stillbirth, shoulder dystocia, born small or large for gestational age, macrosomia, low Apgar score, infant birth trauma, cerebral impact of the infant, neonatal hypoglycaemia, meconium aspiration syndrome and respiratory distress.

Results: Women with both PCOS and GDM have a tendency for higher odds than women with either PCOS or GDM for developing preeclampsia, preterm birth, stillbirth, infant born large for gestational age and infant birth trauma. The adjusted odds ratio for preterm birth in women with PCOS-only were 1.34 (95% CI 1.28–1.41) and GDM-only 1.64 (95% CI 1.39–1.93) and for women with PCOS and GDM 2.08 (95% CI 1.67–2.58).

Conclusions: The combination of PCOS and GDM appears to exacerbate the risk of adverse pregnancy outcomes for both mother and infant compared with women with either PCOS or GDM.

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: Pregnant women often experience subjective sleep disturbances shown to be associated with maternal and fetal outcomes. However, subjectively experienced sleep often deviates from objective measurements. Therefore, the aim of this study was to explore the relationship between objectively measured sleep in early to mid-pregnancy and maternal and fetal outcomes and inflammatory biomarkers.

Methodology: A total of 1,610 pregnant women aged 18 or older from the Safe Physical Activity in Pregnancy (SPAP) study were recruited during early (week 10-14) to mid-pregnancy (week 16-19). Blood samples were taken and sleep was monitored using an Actiwatch, tracking total sleep time, sleep efficiency, wake after sleep onset, and sleep onset latency for 7 days in early to mid-pregnancy. A combined sleep categorisation was created using total sleep time and sleep efficiency to categorise participants into three sleep quality groups: Good, Intermediate, and Poor. Maternal and fetal outcomes were collected via questionnaires, medical records, and plasma samples were analysed using the Olink cardiovascular paneI Il (n = 407).

Results: A total of 1,444 participants were included. The women were categorized as good sleepers (50.4%), intermediate (32.6%), or poor sleepers (17.0%) based on the distribution of the participant's sleep parameters. Poor sleep was more common in women born outside Europe, those with higher pre-gestational BMI, and those with pre-pregnancy diabetes. Sleep groups did not differ in metabolic factors. Poor sleep was associated with an increased likelihood of requiring an emergency caesarean section (AOR = 1.86, 95% CI 1.13-3.05). No significant associations were found for other outcomes such as pre-eclampsia, premature birth, small for gestational age etc. Nine inflammatory biomarkers were significantly lower in poor sleepers, while one marker was higher.

Conclusion: Poor sleep in early to mid-pregnancy was more common in pregnant women with pre-pregnancy diabetes, obesity, and those born outside of Europe. Poor sleep was associated with a higher likelihood of emergency caesarean section, but no other maternal or fetal outcomes. An overall trend was observed towards lower levels of inflammatory markers in women that slept poorly; however, additional studies are needed to better understand the immune system's role in the relationship between sleep, maternal health, and maternal and fetal outcomes. Possible mechanisms underlying these associations warrant further research.

Premenstrual dysphoric disorder (PMDD) affects a subset of women of reproductive age, characterized by severe mood disturbances and physical symptoms during the luteal phase of the menstrual cycle. Symptoms include mood swings, irritability, anxiety, fatigue, physical discomfort, and disruptions to sleep and circadian rhythms, such as altered melatonin secretion. Despite the prevalence of these symptoms, the impact of PMDD treatments on sleep and circadian markers, like melatonin, remains insufficiently understood. This review examines how dysregulated serotonin signaling, disrupted allopregnanolone activity (a neurosteroid derived from progesterone), and aberrant circadian rhythms contribute to PMDD. It also explores the effects of pharmacological treatments, including selective serotonin reuptake inhibitors, on sleep and melatonin regulation, and how these factors influence treatment outcomes. Additionally, the use of hypnotics and sedatives to manage sleep disturbances in PMDD is considered, weighing their potential benefits and risks. A deeper understanding of the interaction between PMDD symptoms, sleep, and circadian rhythms is crucial for developing more effective treatments. Further research is needed to explore the relationship between symptom management, sleep patterns, and circadian function in PMDD, and to determine how these factors can be optimized to improve clinical outcomes and quality of life for women affected by the disorder.

Sex hormones are known to affect brain structure. Given that menopause is marked by a significant decline in female sex hormones, there might be structural brain alterations around menopause. The aim of this article is to provide a narrative review on what we know today with respect to links between brain anatomy and menopause, while also considering potential effects of menopausal hormone therapy (MHT). The review is focused on neuroimaging studies analyzing the macro-anatomy or micro-anatomy of the human brain as based on structural magnetic resonance imaging (MRI) or diffusion tensor imaging (DTI). Out of the 32 studies reviewed here, 22 studies revealed at least some findings that suggest beneficial effects of estrogen. However, overall, findings are rather mixed pointing to both beneficial and adverse effects (or to no effects at all). The nature of the effects seemed to be unrelated to the spatial scales applied, the morphometric measures obtained, and the brain tissues targeted. Nevertheless, there were some intriguing effects in terms of the study design: Cross-sectionally, there seemed to be a trend for beneficial effects in small-scale studies and for adverse effects in large-scale studies. Longitudinally, there seemed to be a trend for beneficial effects in purely observational studies and for beneficial as well as adverse effects in controlled clinical trials. With particular respect to MHT, early treatment (short after the onset of menopause) might be more beneficial than later treatment. However, overall, data are insufficient to draw final conclusions and further research is required.

Background

Premenstrual dysphoric disorder (PMDD) is a depressive disorder triggered by fluctuations of progesterone and estradiol during the luteal phase of the menstrual cycle. Selective progesterone receptor modulation (SPRM), while exerting an antagonistic effect on progesterone and maintaining estradiol on moderate levels, has shown beneficial effects on the mental symptoms of PMDD. Progesterone is also known for its neuroprotective effects, while synthetic progestins have been suggested to promote myelination. However, the impact of SPRM treatment on white matter microstructure is unexplored.

Methods

Diffusion tensor imaging was employed to collect data on white matter integrity in patients with PMDD, before and after treatment with ulipristal acetate (an SPRM) or placebo, as part of a double-blind randomized controlled-trial. Tract based spatial statistics were performed to investigate SPRM treatment vs. placebo longitudinal effects on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), on the whole white matter skeleton.

Results

Voxel-wise analyses indicated no change over time in any white matter microstructure metrics in individuals treated with SPRM versus placebo. Improvement in PMDD symptoms did not correlate with changes in white matter microstructure. In secondary, exploratory, cross-sectional comparisons during treatment, the SPRM group displayed lower FA and higher MD, RD, and AD than the placebo group in several tracts.

Conclusion

The main findings suggest that SPRM treatment did not impact white matter microstructure compared with placebo. However, secondary exploratory analyses yielded between-group differences after treatment, which call for further investigation on the tracts potentially impacted by progesterone antagonism.

Clinical trial registration

EUDRA-CT 2016–001719-19; “Selective progesterone receptor modulators for treatment of premenstrual dysphoric disorder. A randomized, double-blind, placebo-controlled study.”; https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001719-19/SE

Purpose

High-grade serous ovarian cancer (HGSC) is the most common ovarian cancer subtype. Parity is an important risk-reducing factor, but the underlying mechanism behind the protective effect is unclear. Our aim was to study if the expression of hormones and proteins involved in pregnancy were affected by the woman’s parity status, and if they may be associated with tumor stage and survival.

Methods

We evaluated expression of progesterone receptor (PR), progesterone receptor membrane component 1 (PGRMC1), relaxin-2, and transforming growth factor beta 1 (TGFβ1) in tumor tissue from 92 women with HGSC parous (n = 73) and nulliparous (n = 19). Key findings were then evaluated in an independent expansion cohort of 49 patients. Survival rates by hormone/protein expression were illustrated using the Kaplan–Meier method. The independent prognostic value was tested by Cox regression, using models adjusted for established poor-prognostic factors (age at diagnosis, FIGO stage, type of surgery, and macroscopic residual tumor after surgery).

Results

HGSC tumors from parous women were PR positive (≥ 1% PR expression in tumor cells) more often than tumors from nulliparous women (42% vs. 16%; p-value 0.04), and having more children was associated with developing PR positive tumors [i.e., ≥ 3 children versus nulliparity, adjusted for age at diagnosis and stage: OR 4.31 (95% CI 1.12–19.69)]. A similar result was seen in the expansion cohort. Parity status had no impact on expression of PGRMC1, relaxin-2 and TGFβ1. No associations were seen with tumor stage or survival.

Conclusion

Tumors from parous women with HGSC expressed PR more often than tumors from nulliparous women, indicating that pregnancies might possibly have a long-lasting impact on ovarian cancer development.