Biology of Sex Differences最新文献

Background: Alzheimer's disease (AD) exhibits sex differences in pathology and cognitive trajectories. Understanding how these differences manifest across the Alzheimer's continuum can improve early detection, diagnostics, and interventions. We examined sex differences in the association between cerebrospinal fluid (CSF) pTau181/Aβ42 ratio changes and verbal memory decline across the preclinical and mild cognitive impairment (MCI) stages of AD.

Methods: In this retrospective, longitudinal, observational study, data were extracted from 401 participants (age range: 55-87.8, 98% non-Hispanic White) of the Alzheimer's Disease Neuroimaging Initiative cohort study who were classified as either preclinical AD (78 females, 73 males) or MCI (104 females, 146 males) at baseline and had CSF pTau181/Aβ42 ratio and cognitive assessment data at at-least two timepoints. Using regression models, we examined the relationship between changes in CSF pTau181/Aβ42 and verbal memory across all available time points and the moderating role of sex and AD stage over a mean follow-up period of 4 years. Verbal memory was represented by a composite z-score averaging Learning and Delayed Recall z-scores of the Rey Auditory Verbal Learning Test. Covariates included baseline age, education, and apolipoprotein E genotype.

Results: A significant sex * diagnostic group * biomarker change interaction (b=-17.47, 95%CI = 27.60 to -7.33, p = .001) indicated that sex differences in the relationship between changes in CSF pTau181/Aβ42 ratio and verbal memory differed by disease stage. While males in the preclinical AD stage showed steeper memory decline than females with increasing pTau181/Aβ42 ratios, this difference was not statistically significant. In contrast, in the MCI stage, a significant sex * biomarker change interaction (b = 10.17, 95% CI = 4.94 to 15.40, p < .001) indicated that females exhibited significantly steeper memory decline associated with increasing pTau181/Aβ42 ratios compared to males.

Conclusion: Sex differences in the relationship between AD biomarker levels and cognitive decline vary by disease stage. Although not statistically significant, females demonstrated resilience to memory decline in the preclinical stage, whereas, in the MCI stage, they experienced significantly steeper memory loss compared to males. Results suggest that accounting for sex in biomarker-based methods of disease detection and tracking can improve early detection and intervention in both sexes.

Background and aims: Obesity is usually linked to negative outcomes in many diseases; however, some acute critical conditions exhibit a phenomenon known as the obesity paradox. This investigation assessed sex-specific differences in type 2 myocardial infarction (T2MI), a condition caused by an imbalance between oxygen supply and demand in the myocardium and unrelated to atherosclerotic plaque rupture. Additionally, the study explored the implications of body mass index (BMI) in patients with acute ischemic stroke (AIS).

Methods: AIS patients were consecutively enrolled at Jiading District Central Hospital affiliated Shanghai University of Medicine & Health Sciences, from October 1, 2017, to December 31, 2023. Participants were divided into four groups based on their BMI: underweight group, normal weight group, overweight group, and obesity group. The primary outcome of the study was the incidence of T2MI. We employed Cox regression analysis and Kaplan-Meier curves to examine the relationship between BMI and the occurrence of T2MI. Additionally, we performed a restricted cubic spline (RCS) analysis to evaluate the linearity of this relationship, utilizing an iterative algorithm to pinpoint inflection points. The subgroup forest plot displays how the four BMI groups vary across different layers.

Results: The incidence of T2MI was 4.43%(131/2995) in AIS patients. After adjusting for potential confounding variables, the risk of T2MI was higher in the normal-weight group (HR, 2.11; 95% CI, 1.36-3.26; p < 0.001) compared to the obese group. In female patients, the risk of T2MI was higher in both the normal-weight group (HR, 3.47; 95% CI, 1.64-7.36; P = 0.001) and the underweight group (HR, 4.06; 95% CI, 1.44-11.44; P = 0.008) compared to the obese group; however, no such association was found in male patients. Furthermore, the RCS analysis confirmed a linear correlation between BMI and the risk of T2MI.

Conclusions: The association between BMI and T2MI in AIS patients varied between genders. Obese female AIS patients had a lower risk of T2MI, a trend that was not mirrored in their male counterparts. These findings underscore the importance of considering sex-specific factors in understanding the complex relationship between obesity and T2MI in patients with AIS.

Objective: To assess the impact of sex on mortality and malignancy in patients with primary Sjögren's disease (pSD).

Methods: This ambispective cohort study included 1,182 pSD patients (1,025 women and 157 men) from the China-Japan Friendship Hospital between 2014-2023 and followed through 2024. Survival outcomes were estimated via Kaplan-Meier curves, and SMRs were calculated. Independent risk factors were identified via multivariate Cox regression, followed by stepwise Cox, sex-stratified and interaction analyses.

Results: During follow-up, 125 deaths (10.6%) and 33 malignancies (2.8%) occurred, both of which were more common in men (log-rank tests, P < 0.001). Overall mortality was markedly higher in men (25.5%, SMR = 4.79) than in women (8.3%, SMR = 2.42). Male sex was independently associated with higher risk of mortality (HR = 1.998, P = 0.004) and cancer incidence (HR = 3.799, P = 0.001). Sex-stratified analyses revealed distinct death-associated factors: interstitial lung disease (ILD), pulmonary infection and ischemic stroke were independently associated with mortality in men, whereas older age, low C3, elevated C-reactive protein and total bilirubin (TBIL) levels were associated with mortality in women. With respect to cancer, longer disease duration, lymphadenopathy, lymphocytopenia, elevated TBIL and hypochloremia were independently associated with cancer risk in women, whereas no variables showed an independent association with cancer risk among men. Interaction analyses demonstrated additive interactions between male sex and elevated ESSDAI scores, as well as male sex and concomitant ILD, in relation to mortality.

Conclusion: Compared with women, men with pSD presented greater risks and distinct risk profiles of death and malignancy. Moreover, male sex was independently associated with adverse outcomes and acted as an important effect modifier, highlighting the need for sex-specific risk stratification and clinical management.

Trial registration: This ambispective cohort study was registered in the Clinical Trial Registry (ID: NCT06528197) on June 27, 2024 and conducted in accordance with the Declaration of Helsinki.

Background: The relationship between obstructive sleep apnea (OSA) and thyroid hormone sensitivity remains unclear. Thyroid hormone sensitivity indices may reveal subclinical hypothalamic-pituitary-thyroid (HPT) axis dysregulation beyond conventional hormone levels.

Methods: We analyzed 718 euthyroid adults who underwent overnight sleep monitoring, using thyroid‑stimulating hormone index (TSHI), thyroid feedback quantile-based index (TFQI), parametric thyroid feedback quantile-based index (PTFQI), thyrotroph T4 resistance index (TT4RI), thyrotroph T3 resistance index (TT3RI) and the ratio of free triiodothyronine to free thyroxine (FT3/FT4 ratio) to assess central and peripheral thyroid hormone sensitivity. Analysis of covariance assessed differences across OSA severity after adjusting for age and BMI. Multivariable linear regression examined associations between OSA severity and thyroid hormone sensitivity indices in sex-stratified models. Correlations between OSA-related parameters and thyroid hormones sensitivity indices were further explored using quadratic prediction plots.

Results: Among females, OSA patients showed higher FT4 and significantly increased TFQI, PTFQI, TSHI, and TT4RI, but lower FT3/FT4 ratio compared with non-OSA. TFQI (P for trend = 0.0395) and TT4RI (P for trend = 0.0293) were positively correlated with increasing OSA severity. OSA was independently associated with elevated TFQI (β = 0.26, 95% CI 0.010-0.42, P = 0.001), PTFQI (β = 0.20, 95% CI 0.05-0.35, P = 0.011), TSHI (β = 0.24, 95% CI 0.03-0.44, P = 0.025), and TT4RI (β = 6.82, 95% CI 0.59-13.05, P = 0.033). apnea-hypopnea index (AHI), oxygen desaturation index (ODI) were significantly correlated with TT4RI (P = 0.034, 0.021, respectively). No significant associations were observed in males.

Conclusions: OSA is associated with impaired central and peripheral thyroid hormone sensitivity in euthyroid females, but not in males.

Background: Hypertension is a polygenic, complex disease that impacts men and women differently; whilst the incidence of high blood pressure (BP) is roughly equal over a lifetime, men typically are at higher risk of developing the disease earlier in life, before 50 years of age. There is adequate evidence that the brain is critical for the BP setpoint. The paraventricular nucleus (PVN) of the hypothalamus is an integrative structure that can influence not only neurohumoral responses to blood pressure changes, but also sympathetic drive. Here we manipulate the androgenic status of both male and female spontaneously hypertensive rats (SHRs) to determine how this changes gene expression within the PVN of these animals.

Methods: SHR (8-weeks old) were either sham-operated or orchiectomized, whereas all females were oophorectomized, half of which received 10 mg testosterone propionate subcutaneously. Mean arterial pressure (MAP) and testosterone (T) were measured by carotid cannulation and ELISA respectively. Sequencing was performed on hand-punched PVN sections and subjected to robust bioinformatic analysis.

Results: in total, 6,571 differentially regulated genes (DRGs) are regulated in the PVN of male and female rats. High T (endogenous or replaced) correlates with higher MAP in both sexes. Orchidectomy-induced T depletion resulted in the significant regulation of 5,104 genes, involved in thousands of biological roles, including ones related to hormone and sex-hormone signalling. In the female SHR, testosterone replacement in oophorectomized animals induced the regulation of 1,727 genes, sharing many biological functions with those in the high T males. We validated key genes by qPCR to determine false discovery rate.

Conclusions: T status in hypertensive rats correlates with MAP, and consistent changes in PVN transcriptome.

Background: Alzheimer's disease (AD) remains the most prevalent cause of dementia, yet no existing treatment effectively prevents its onset. Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.

Methods: Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.

Results: Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.

Conclusions: These findings highlight ULD-THC's potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.

Background: To compare the effectiveness of romosozumab (ROMO) with parathyroid hormone (PTH) receptor agonists [teriparatide (TPTD)/abaloparatide (APTD)] in reducing fracture risk following osteoporosis treatment.

Methods: A TriNetX cohort study assessed fracture and mortality risks using Kaplan-Meier analysis with hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: After propensity score matching (n = 2,258 pairs), ROMO users had lower risks of osteoporotic fractures (HR: 0.711, 95% CI: 0.542-0.931) and hypercalcemia (HR = 0.707, 95% CI: 0.511-0.977) compared with PTH receptor agonists. Five subgroup analyses demonstrated a reduced fracture risk in the ROMO cohort among women (HR: 0.738), patients aged ≥ 65 years (HR: 0.652), individuals with a history of prior fractures (HR: 0.659), and those without chronic kidney disease (CKD) (HR: 0.731). Sensitivity analyses confirmed the robustness of the findings across different covariate adjustments, data sources, and extended follow-up, consistently showing a lower risk of hypercalcemia and nonsignificant trends toward reduced fracture risk in the ROMO cohort.

Conclusion: Compared with PTH analogs, ROMO offers stronger short-term protection against osteoporotic fractures and hypercalcemia, particularly in older women with prior fractures. Nonetheless, cardiovascular safety, calcium metabolism, and sequential therapy require careful consideration for individualized treatment.

This review takes a close look at the biology of brown and beige fat, not just as thermogenic tissues, but as active metabolic organs influenced by sex, hormones, age, and even environment. Brown adipose tissue (BAT) and beige adipocytes differ in their origins, gene expression, and regulation. These differences are especially relevant when considering how they behave in males and females. Across both animal and human studies, females show higher BAT volume and more efficient thermogenic activity. Estrogen, acting mainly through estrogen receptor alpha (ERα), increases uncoupling protein 1(UCP1) expression, promotes mitochondrial biogenesis, and supports the formation of beige fat within white adipose tissue. In contrast, testosterone and glucocorticoids tend to reduce thermogenic gene expression and shift fat storage toward visceral depots, which increases metabolic risk, particularly in men. These hormone-driven effects are not limited to adulthood. Puberty, pregnancy, menopause, and andropause all influence thermogenic capacity in sex-specific ways. We also outline the key signaling pathways behind beiging such as PR domain-containing 16 (PRDM16), Peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), and β3-adrenergic signaling and how they interact with sex hormones to shape thermogenic responses. Findings from Positron Emission Tomography with Computed Tomography (PET/CT) imaging, genetic models, and molecular profiling show that beige and brown fat are regulated by distinct mechanisms and developmental cues depending on sex. We also review how BAT activity is linked to a lower risk of type 2 diabetes, cardiovascular disease, and inflammation, particularly in women with obesity. Conditions like Polycystic Ovary Syndrome (PCOS), hormone therapy, and exposure to endocrine-disrupting chemicals further influence BAT function in sex dependent ways. Understanding how brown and beige fat respond differently in men and women to internal and external signals, is critical. These differences have clear implications for developing targeted, more effective strategies to treat obesity and metabolic disease.