Biology of Sex Differences最新文献

Background: Hypertensive disorders of pregnancy (HDP) are associated with worse prenatal and perinatal sleep health and higher cardiovascular disease risk beyond the peripartum period. The relationship of HDP with sleep health in midlife, when sleep problems are common, remains unclear.

Methods: We studied women enrolled in Project Viva during early pregnancy (1999-2002) with sleep outcomes assessed in midlife (2017-2024). We determined lifetime HDP via medical records from the index pregnancy and self-report both at enrollment and during midlife. Outcomes were (i) self-reported sleep duration and sleep quality, using the patient-reported outcomes measurement information system sleep disturbance and sleep-related impairment instruments at mean 52.3yrs; and (ii) objectively measured 5-day sleep duration and efficiency by wrist actigraphy at mean 55.8yrs in a subset. We performed linear and logistic regression models adjusted for enrollment age, education, parity, household income, pre-pregnancy BMI, race, and ethnicity and considered modification by social determinants of health.

Results: Of 767 participants, 23% had a lifetime history of HDP, 4% had ≥ 2 episodes, and 7% had HDP during their last pregnancy. Mean (SD) daily sleep duration was 7.1 (1.0) hours by self-report and 6.7 (1.0) hours by actigraphy. Any (vs. no) lifetime HDP was associated with shorter self-reported (-8 min, 95% CI: -19, 2) and actigraphy-measured (-16 min, 95% CI: -31, -1) sleep duration. Estimates were stronger but with wider CIs for those with ≥ 2 (vs. no) HDP episodes (e.g., -23 min, 95% CI: -53, 6 for actigraphy-measured sleep duration). Mean (SD) sleep disturbance T-score was 48.6 (7.4) and sleep-related impairment was 45.8 (8.5). Any lifetime HDP (vs. none) was associated with higher (worse) sleep disturbance T-score (1.85 points, 95% CI: 0.28, 3.42) with stronger associations for ≥ 2 HDP episodes (3.41 points, 95% CI: 0.17, 6.65) and for HDP in the last pregnancy (3.63 points, 95% CI: 0.70, 6.57). HDP was not associated with self-reported sleep-related impairment or sleep efficiency.

Conclusions: History of HDP was associated with shorter sleep duration and higher sleep disturbance in midlife. Future work should investigate the contribution of sleep health to associations of HDP exposure with cardiovascular disease risk in later life.

Stress triggers many responses including behavioral strategies to cope with the environment and to maintain homeostasis. Notably, the experience of stressful events is highly subjective. In fact, in susceptible individuals, primary adaptation responses can fail leading to maladaptive mechanisms and to the subsequent development of stress-related disorders (e.g., post-traumatic stress disorder; PTSD). However, the mechanisms underlying interindividual variability in stress adaptation are still to be elucidated. Animal models are widely recognized as essential scientific tools to understand the neurobiological underpinnings of stress susceptibility/resilience, and as tools to identify novel and personalized interventions to treat (and prevent) such disorders in humans. Experimental models have however several limitations, as validity criteria can be very problematic when modeling psychiatric disorders. Also, while sex dimorphism crucially contributes to the risk for stress-related diseases, several frequently used models overlooked sex differences in the interindividual variability in response to stress. In this review, we describe the interindividual and sex differences in susceptibility and resilience in stress-related disorders, with a particular focus on PTSD. Further, we examine aspects of animal models of PTSD that can be improved to obtain higher translational value.

Background: Gender-affirming testosterone therapy (GATT) use may be associated with increased systolic blood pressure (SBP). The association between serum testosterone and cardiovascular health in individuals using GATT is unknown. The objective of this study was to estimate the association between serum testosterone and validated measures of cardiovascular health, including SBP and arterial stiffness, in persons assigned female sex at birth using GATT.

Methods: Healthy participants assigned female sex at birth on a stable GATT regimen for ≥ 4 months were recruited to this community-partnered exploratory cross-sectional study. Exposures of interest were total and free serum testosterone concentration. As our primary outcome, SBP was measured by an automated sphygmomanometer, and carotid-radial pulse wave velocity (PWVcr) and aortic augmentation index (AIx) were used to measure arterial stiffness via applanation tonometry.

Results: Participants (n = 18, median age 28 years, range: 18, 50) who predominantly self-identified as white (94%) and had been using GATT for a median of 48 months (range: 5, 84) were studied. Resting SBP, PWVcr, and AIx were 113 mmHg (range: 102, 129), 7 m/s (range: 4, 9), and 9% (range: - 10, 23), respectively. Total and free serum testosterone were not significantly associated with SBP or PWVcr. Free, but not total, serum testosterone was positively associated with AIx (p = 0.03). Sensitivity analyses did not modify any results.

Conclusions: In healthy transgender individuals, serum testosterone concentrations may not be associated with measures of cardiovascular health. However, these results need to be interpreted with caution given the limited sample size.

Background: Takotsubo Syndrome (TTS) is an acute form of heart failure that disproportionately impacts post-menopausal women. The brain-heart connection is considered a pathway for TTS pathophysiology leading to investigations of the role of psychological, psychosocial, and personality factors in TTS.

Objectives: We compare psychosocial characteristics among a subset of individuals with confirmed TTS and those who had symptoms adjudicated as non-TTS in our online Takotsubo registry (n = 104). We also evaluate differences in TTS clinical characteristics among those with and without symptoms of PTSD and depression.

Methods: The Smidt Heart Institute Takotsubo registry enrolls individuals with a history of TTS sourced through physician referrals, medical records review, peer- and self-referrals. Psychosocial characteristics were assessed using questionnaires validated in acute coronary syndrome populations. Hedge's g effect sizes were computed to compare differences in perceived stress, depression symptoms, and post-traumatic stress disorder (PTSD) symptoms relative to TTS status.

Results: Compared to participants confirmed to be non-TTS, those with adjudication-confirmed TTS had worse mean psychosocial scores (indicative of worse psychosocial characteristics). After adjusting for age at event, BMI, race, and smoking status, the Hedge's g effect size for depressive symptoms was moderate [0.60 (-0.03, 1.22)] while effect sizes for other psychosocial measures were minimal (Trait anxiety: [0.01 (-0.58, 0.60)], PTSD symptoms [0.13 (-0.46, 0.73)], perceived stress [0.06 (-0.53, 0.65)]. Effect sizes were relatively lower following adjustment, largely driven by participants' age at first event. Individuals with elevated PTSD symptoms were significantly younger at their first TTS event compared to those with minimal or no symptoms (54 ± 8 vs. 61 ± 10; p = 0.005). QTc was relatively longer among individuals with elevated PTSD symptoms (483 ± 40 msec vs. 465 ± 32 msec; p = 0.08) and elevated depressive symptoms (481 ± 33 msec vs. 464 ± 36 msec; p = 0.07), although the differences were not statistically significant.

Conclusions: Psychosocial characteristics including PTSD, depression, and stress are common among women with TTS, and age at the time of TTS event is a potentially important moderator of this relationship. We did not find Trait-anxiety or early childhood trauma to be associated with TTS in our cohort.

Background: Certain events that occur in early life, such as changes in nutrition, can promote structural and functional modifications in brain development, projecting to either short, medium, and/or long terms, resulting in metabolic programming. These effects depend on the timing, intensity, and duration of exposure, and are proposed to be the cause or contribute to chronic adult disorders. Recent studies have proposed that artificial non-nutritive sweeteners (NNS), such as saccharin, can be included as one of these developmental disruptors. Saccharin consumption during pregnancy is strongly discouraged, as it can cross through the placenta and accumulate in the fetus, potentially impacting metabolic control for life. However, the mechanisms underlying the metabolic syndrome induced by maternal NNS consumption during pregnancy are not well understood. Some studies suggest that NNS may affect sweet taste receptors in the adult's guts, leading to changes in the release of glucagon-like peptide-1 (GLP-1) and insulin. The objective of the study is to investigate whether maternal saccharin consumption during pregnancy affects the gut-brain connection, leading to alterations in insulin/GLP-1 signaling during neurodevelopment until adolescence.

Methods: Pregnant rats were administered 0.1% saccharin in drinking water throughout gestation, and the main components of the insulin/GLP-1 signaling pathway were analyzed in the plasma, small intestine and hypothalamus of the offspring after weaning. Perinatal exposure to saccharin was linked to disrupted glucose homeostasis and insulin sensitivity in both male and female offspring.

Results: We identified sex-dependent mechanisms that affected GLP-1 signaling in the intestine, associated with the expression of taste receptors and glucose transporters. These alterations affected the gut-brain axis and disrupted hypothalamic signaling associated with glucose regulation and food intake, primarily involving the GLP-1, leptin, and insulin signaling pathways.

Conclusions: These results suggest that developmental NNS exposure might contribute to the growing alteration in energy metabolism.

Background: Chronic liver disease is a major health concern, but sex-specific differences in its pathophysiology remain unclear. Preclinical studies have predominantly used male animals, limiting findings' relevance to both sexes. This project aimed to explore sex differences in cirrhosis and portal hypertension (PH) in rats, and to find similarities in human samples for translational relevance.

Methods: Advanced chronic liver disease (ACLD) was induced in male and female Sprague-Dawley rats using thioacetamide (TAA, 250 mg/kg; 12 weeks) or bile duct ligation (BDL; 28 days). Healthy rats served as controls (n = 11-18/group). We assessed in vivo hepatic and systemic hemodynamic parameters, hepatic microvascular function, and hepatic transcriptomic analyses, including sex-specific differences in cellular composition using gene deconvolution (n = 5/group). Two human sample cohorts were compared to preclinical data for translational insights.

Results: Both animal models showed PH. TAA males had similar portal pressure (PP) to females (14.2 vs 14.1 mmHg), but BDL males had significantly higher PP than females (14.5 vs 12.5 mmHg; p = 0.003). No differences were observed in hepatic microvascular function. In the BDL model, females had more fenestrae and porosity, and less fibrosis. Transcriptomic analysis revealed that TAA males had dysregulated metabolic pathways, while females had deregulated genes in hormone signaling. In the BDL model, males showed higher deregulation in platelet activation, protein degradation, vesicular transport, and disease-related pathways. Gene deconvolution showed males had a more specialized endothelial phenotype basally, with more changes in endothelial and macrophage phenotypes after injury. In MASLD patients, men had dysregulated metabolic pathways, while women showed deregulation in fibrosis, extracellular matrix, and endocrine regulation. In HBV patients, men had more dysregulation in fibrosis, inflammation, and immune response. Female MASLD patients had more activated hepatic stellate cells, and greater loss of endothelial phenotype compared to men.

Conclusions: This study highlights sex-dependent molecular differences in the pathophysiology of cirrhosis in two preclinical models. Further research in preclinical and human liver disease is essential to develop safe and effective treatments for ACLD in both sexes.

Objective: Social determinants of health (SDOH) can have a significant impact on women's health and quality of life. Little is known about the impact of SDOH during menopause, and whether certain SDOH impact the likelihood of using systemic hormone therapy (HT). Our objective was to evaluate the impact of SDOH on the likelihood of HT utilization among midlife women.

Design: Midlife women between the ages of 45-60 years were surveyed about their menopause experience between March and June of 2021. The questionnaire included information on medications used to treat menopause symptoms. From the electronic medical record demographic information and self-reported SDOH data were obtained, including the amount of exercise/physical activity, whether the participants felt stressed, social interactions, abuse in the last year, ability to pay for basics, diet, alcohol intake, smoking status, and whether participants had regular dentist visits. SDOH were compared between using/not using HT currently.

Results: One thousand nine hundred and eighty-eight women aged 45-60 years who received primary care at one of four geographic Mayo Clinic sites completed the survey and filled out SDOH questions within 2 years. Women were 54.4 years of age on average (SD 4.2), with a mean BMI of 30.2 (SD 7.5), and a majority White (97%). 258 (13.0%) women were currently using HT. In univariate analysis, women were less likely to be using HT if they had higher BMI (per 1 kg/m² increase, OR = 0.97, 95% 0.95-0.99, p = 0.002) were unpartnered (OR = 0.66, 95% CI 0.45-0.99, p = 0.04) had lower education (compared to post graduate studies, high school graduate/GED or less: OR = 0.45, 95% CI 0.24-0.85, p = 0.01; some college/2 year degree: OR = 0.69, 95% CI 0.49-0.96,p = 0.03), or were a smoker (compared to those who never smoked, current smoker: OR = 0.38, 95% CI 0.18-0.83, p = 0.02; former smoker: OR = 0.71, 95% CI 0.52-0.96, p = 0.03). Women who used extra virgin olive oil as main fat in diet were more likely to be using HT (OR = 1.46, 95% CI 1.10-1.94, p = 0.009). No other SDOH were associated with HT.

Conclusion: Certain SDOH were associated with HT use for menopause treatment. Favorable SDOH likely correlate with better access to menopause care. To assure equitable menopause treatment for all women, clinicians should evaluate and address SDOH with their midlife women patients.

Background: Elevated ovarian hormones during fear extinction can enhance fear extinction memory retention and reduce fear renewal, but the mechanisms remain unknown. High levels of ovarian hormones are associated with heightened dopamine (DA) transmission, a key player in fear extinction. In males, stimulation of substantia nigra (SN) DA neurons during fear extinction reduces renewal; an effect mimicked by DA D1 receptor agonist administration into the dorsolateral striatum (DLS), a primary target of the SN. The current studies tested the role of the SN-DLS pathway in estrous cycle-modulation of fear extinction and relapse.

Methods: Male and female Long-Evans rats were used to investigate the effects of sex and ovarian hormone levels during fear extinction on later fear relapse and underlying mechanisms. Fear extinction-induced cFos in SN DA neurons was quantified with double-label immunohistochemistry. An intersectional chemogenetic approach was used to determine whether SN-DLS pathway activity during fear extinction is necessary and sufficient for observed effects of ovarian hormones on fear relapse. Finally, fast scan cyclic voltammetry revealed the effects of sex and ovarian hormones on electrically-evoked DA release in the DLS and verified the effectiveness of chemogenetic approaches.

Results: Female rats exposed to fear extinction during proestrus or estrus (Pro/Est; high hormones) had less relapse (renewal and spontaneous recovery) compared to males or females exposed to fear extinction during metestrus or diestrus (Met/Di; low hormones). Fear extinction-induced cFos within SN DA neurons and electrically-evoked DA release in the DLS was highest in female rats during Pro/Est. The behavioral and neurochemical effects of Pro/Est were mimicked by estradiol administration to ovariectomized female rats. Inhibition of the SN-DLS pathway suppressed electrically-evoked DA release in the DLS and restored fear renewal in females exposed to simultaneous fear extinction and SN-DLS inhibition during Pro/Est. Conversely, stimulation of the SN-DLS pathway during extinction reduced fear renewal in males.

Conclusions: Results indicate that ovarian hormones present during fear extinction reduce later fear relapse through a SN-DLS dopamine pathway. Data suggest the SN-DLS DA pathway is a novel target for the reduction of fear relapse in both sexes.