RESUMEN

Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID1, similar to observations in other infections2. Females respond more strongly to vaccines, and adverse reactions are more frequent3, like most autoimmune diseases4. Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6-8. In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells. These findings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals.

Asunto(s)

Testosterona , Personas Transgénero , Adulto , Femenino , Humanos , Masculino , Conjuntos de Datos como Asunto , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Sistema Inmunológico/metabolismo , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-15/inmunología , Interleucina-15/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Monocitos/inmunología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/metabolismo , Caracteres Sexuales , Testosterona/efectos adversos , Testosterona/inmunología , Testosterona/farmacología , Testosterona/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

Adolescence is a period of substantial social-emotional development, accompanied by dramatic changes to brain structure and function. Social isolation due to lockdowns that were imposed because of the COVID-19 pandemic had a detrimental impact on adolescent mental health, with the mental health of females more affected than males. We assessed the impact of the COVID-19 pandemic lockdowns on adolescent brain structure with a focus on sex differences. We collected MRI structural data longitudinally from adolescents prior to and after the pandemic lockdowns. The pre-COVID data were used to create a normative model of cortical thickness change with age during typical adolescent development. Cortical thickness values in the post-COVID data were compared to this normative model. The analysis revealed accelerated cortical thinning in the post-COVID brain, which was more widespread throughout the brain and greater in magnitude in females than in males. When measured in terms of equivalent years of development, the mean acceleration was found to be 4.2 y in females and 1.4 y in males. Accelerated brain maturation as a result of chronic stress or adversity during development has been well documented. These findings suggest that the lifestyle disruptions associated with the COVID-19 pandemic lockdowns caused changes in brain biology and had a more severe impact on the female than the male brain.

Asunto(s)

Encéfalo , COVID-19 , Imagen por Resonancia Magnética , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , COVID-19/psicología , Femenino , Masculino , Adolescente , Encéfalo/diagnóstico por imagen , Encéfalo/crecimiento & desarrollo , SARS-CoV-2 , Pandemias , Factores Sexuales , Aislamiento Social , Caracteres Sexuales , Cuarentena , Salud Mental , Niño , Desarrollo del Adolescente

RESUMEN

Post-traumatic stress disorder (PTSD) presents distinct sex-specific differences in both symptom expression and treatment outcomes, with the underlying biological mechanisms still remain unclear. Epigenetic modifications, particularly histone acetylation, have been increasingly recognized as critical factors in the pathophysiology of PTSD. Valproic acid (VPA), a potent histone deacetylase (HDAC) inhibitor, has shown promise in modulating epigenetic responses and improving therapeutic outcomes is PTSD, though its effect may differ between sexes. This study aimed to explore the sex-specific epigenetic changes in response to trauma and the impact of VPA treatment in a rat model of PTSD induced by predator scent stress. Sprague-Dawley rats of both sexes were randomly assigned to stressed and non-stressed groups and treated with either VPA (100 mg/kg) or vehicle. Anxiety levels were assessed using the elevated plus maze, followed by analysis of histone H3 and H4 acetylation, HDAC activity, and c-fos expression in the hippocampus. Our findings revealed that traumatic stress led to increased freezing time and anxiety levels, with more pronounced effects observed in females. Additionally, we have identified sex-specific differences in hippocampal epigenetic modifications; stressed females exhibited higher H3 acetylation, and VPA-treated stressed males showed increased H4 acetylation. These results highlight the importance of considering sex differences in the epigenetic mechanism underlying PTSD and suggest that personalized therapeutic approaches may be necessary to address these complexities.

Asunto(s)

Epigénesis Genética , Inhibidores de Histona Desacetilasas , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático , Ácido Valproico , Animales , Ácido Valproico/farmacología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/metabolismo , Masculino , Femenino , Epigénesis Genética/efectos de los fármacos , Ratas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Modelos Animales de Enfermedad , Histonas/metabolismo , Caracteres Sexuales , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Acetilación/efectos de los fármacos , Ansiedad/tratamiento farmacológico

RESUMEN

BACKGROUND: We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine. METHODS: Male and female C57BL6J mice received either supradural orexin B and an inflammatory mediator cocktail (IM) with migraine-like pain behaviors and photophobia recorded. Expression of orexin 2 receptor (OX2R) in trigeminal ganglion (TG) and phosphorylated extracellular signal-regulated kinases (ERK) levels in trigeminal nucleus caudalis (TNC) were evaluated. Orexin B-induced excitability of TG cells was assessed with patch-clamp electrophysiology. Intranasal delivery of CRISPR/Cas9 plasmids was used to edit the expression of OX2R in the TG. RESULTS: Supradural orexin B induced migraine-like pain behaviors, photophobia and increased TNC ERK phosphorylation exclusively in males. Blockade of orexin signaling with supradural suvorexant, a dual orexin receptor antagonist, prevented, but did not reverse, migraine-like pain in males induced by supradural IM cocktail. OX2R expression was higher in male TG and orexin B increased TG neuron excitability in males. Intranasal OX2R CRISPR/Cas9 reduced TG receptor expression and orexin B-induced TNC ERK phosphorylation and prevented migraine-like pain induced by supradural orexin B in males. CONCLUSIONS: Our studies reveal a male-specific mechanism of TG nociceptor sensitization and migraine-like pain behavior mediated by orexin B/OX2R signaling. Sexually dimorphic mechanisms of trigeminal nociceptor sensitization and activation offer opportunities to improve patient outcomes by considering patient sex and may influence clinical trial design and interpretation.

Asunto(s)

Ratones Endogámicos C57BL , Trastornos Migrañosos , Receptores de Orexina , Ganglio del Trigémino , Animales , Masculino , Femenino , Ratones , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Receptores de Orexina/metabolismo , Receptores de Orexina/genética , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Meninges/efectos de los fármacos , Meninges/metabolismo , Caracteres Sexuales , Orexinas/metabolismo

RESUMEN

Morphological femininity depends mainly on estrogen levels at puberty and is perceived as a cue of a woman's biological condition. Due to the immunostimulant properties of estradiol, estradiol-dependent feminine traits are expected to be positively related to immunity. However, heightened immunity in women may increase the risk of autoimmune disease, thus the relationship between femininity and immune quality may be complex. This study aimed to assess the relationship between morphological femininity and both the occurrence and severity of Hashimoto thyroiditis (HT) in women of reproductive age. Moreover, 95 women with HT and 84 without HT (all between 20 and 37 years) participated in the study. Morphological femininity was assessed based on somatic measurements of sexually dimorphic traits (2D:4D ratio, WHR, breast size, facial sexual dimorphism). The occurrence and severity of HT were assessed by serum TPOAb levels. The results showed that only the 2D:4D ratio of the right hand was higher in the HT group, indicating higher femininity in these women. However, there was also a positive relationship between facial femininity and TPOAb level in women with HT, indicating a higher severity of the disease. The results suggest that prenatal and pubertal exposure to estrogens may increase the probability or severity of autoimmune diseases in adulthood, but the relationship is tentative.

Asunto(s)

Enfermedad de Hashimoto , Humanos , Femenino , Enfermedad de Hashimoto/inmunología , Adulto , Adulto Joven , Feminización , Inmunocompetencia , Feminidad , Caracteres Sexuales

RESUMEN

There are controversies regarding the impact of sex on mortality and postoperative complications in patients undergoing on-pump coronary artery bypass grafting (CABG), although some studies demonstrate comparable outcomes. This study sought to evaluate sex differences regarding risk factors associated with hospital mortality and postoperative clinical outcomes among patients undergoing isolated on-pump CABG. We conducted a retrospective observational cohort study of patients who underwent isolated on-pump CABG from January 1996 to January 2020. Patients were divided into two groups (male and female) and compared regarding preoperative characteristics, surgical technical variables, and in-hospital outcomes. All-cause mortality between groups was compared using logistic regression. Risk factors for mortality, along with their respective odds ratios (OR), were separately assessed using a logistic regression model with p-values for interaction. We analyzed 4,882 patients, of whom 31.6% were female. Women exhibited a higher prevalence of age >75 years (12.2% vs 8.3%, p<0.001), obesity (22.6% vs 11.5%, p<0.001), diabetes (41.6% vs 32.2%, p<0.001), hypertension (85.2% vs 73.5%, p<0.001), and NYHA functional classes 3 and 4 (16.2% vs 11.2%, p<0.001) compared to men. Use of the mammary artery for revascularization was less frequent among women (73.8% vs 79.9%, p<0.001), who also received fewer saphenous vein grafts (2.17 vs 2.27, p = 0.002). A history of previous or recent myocardial infarction (MI) had an impact on women's mortality, unlike in men (OR 1.61 vs 0.94, p = 0.014; OR 1.86 vs 0.99, p = 0.015, respectively). After adjusting for several risk factors, mortality was found to be comparable between men and women, with an OR of 1.20 (95% CI 0.94-1.53, p = 0.129). In conclusion, female patients undergoing isolated on-pump CABG presented with a higher number of comorbidities. Previous and recent MI were associated with higher mortality only in women. In this cohort analysis, female gender was not identified as an independent risk factor for outcome after CABG.

Asunto(s)

Puente de Arteria Coronaria , Mortalidad Hospitalaria , Complicaciones Posoperatorias , Humanos , Masculino , Femenino , Anciano , Puente de Arteria Coronaria/efectos adversos , Puente de Arteria Coronaria/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Resultado del Tratamiento , Enfermedad de la Arteria Coronaria/cirugía , Enfermedad de la Arteria Coronaria/mortalidad , Caracteres Sexuales

RESUMEN

BACKGROUND: Over the past three decades, our understanding of sleep apnea in women has advanced, revealing disparities in pathophysiology, diagnosis, and treatment compared to men. However, no real-life study to date has explored the relationship between mask-related side effects (MRSEs) and gender in the context of long-term CPAP. METHODS: The InterfaceVent-CPAP study is a prospective real-life cross-sectional study conducted in an apneic adult cohort undergoing at least 3 months of CPAP with unrestricted mask-access (34 different masks, no gender specific mask series). MRSE were assessed by the patient using visual analog scales (VAS). CPAP-non-adherence was defined as a mean CPAP-usage of less than 4 h per day. The primary objective of this ancillary study was to investigate the impact of gender on the prevalence of MRSEs reported by the patient. Secondary analyses assessed the impact of MRSEs on CPAP-usage and CPAP-non-adherence depending on the gender. RESULTS: A total of 1484 patients treated for a median duration of 4.4 years (IQ25-75: 2.0-9.7) were included in the cohort, with women accounting for 27.8%. The prevalence of patient-reported mask injury, defined as a VAS score ≥ 5 (p = 0.021), was higher in women than in men (9.6% versus 5.3%). For nasal pillow masks, the median MRSE VAS score for dry mouth was higher in women (p = 0.039). For oronasal masks, the median MRSE VAS score for runny nose was higher in men (p = 0.039). Multivariable regression analyses revealed that, for both women and men, dry mouth was independently and negatively associated with CPAP-usage, and positively associated with CPAP-non-adherence. CONCLUSION: In real-life patients treated with long-term CPAP, there are gender differences in patient reported MRSEs. In the context of personalized medicine, these results suggest that the design of future masks should consider these gender differences if masks specifically for women are developed. However, only dry mouth, a side effect not related to mask design, impacts CPAP-usage and non-adherence. TRIAL REGISTRATION: INTERFACEVENT IS REGISTERED WITH CLINICALTRIALS.GOV (NCT03013283).FIRST REGISTRATION DATE IS 2016-12-23.

Asunto(s)

Presión de las Vías Aéreas Positiva Contínua , Máscaras , Humanos , Presión de las Vías Aéreas Positiva Contínua/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Máscaras/efectos adversos , Estudios Transversales , Anciano , Apnea Obstructiva del Sueño/terapia , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/fisiopatología , Factores de Tiempo , Adulto , Factores Sexuales , Cooperación del Paciente , Estudios de Cohortes , Caracteres Sexuales

RESUMEN

BACKGROUND: Blotched snakehead (Channa maculata) displays significant sexual dimorphism, with males exhibiting faster growth rates and larger body sizes compared to females. The cultivation of the all-male population of snakeheads holds substantial economic and ecological value. Nonetheless, the intricate processes governing the development of bipotential gonads into either testis or ovary in C. maculata remain inadequately elucidated. Therefore, it is necessary to determine the critical time window of sex differentiation in C. maculata, providing a theoretical basis for sex control in production practices. METHODS: The body length and weight of male and female C. maculata were measured at different developmental stages to reveal when sexual dimorphism in growth initially appears. Histological observations and spatiotemporal comparative transcriptome analyses were performed on ovaries and testes across various developmental stages to determine the crucial time windows for sex differentiation in each sex and the sex-related genes. Additionally, qPCR and MG2C were utilized to validate and locate sex-related genes, and levels of E2 and T were quantified to understand sex steroid synthesis. RESULTS: Sexual dimorphism in growth became evident starting from 90 dpf. Histological observations revealed that morphological sex differentiation in females and males occurred between 20 and 25 dpf or earlier and 30-35 dpf or earlier, respectively, corresponding to the appearance of the ovarian cavity or efferent duct anlage. Transcriptome analyses revealed divergent gene expression patterns in testes and ovaries after 30 dpf. The periods of 40-60 dpf and 60-90 dpf marked the initiation of molecular sex differentiation in females and males, respectively. Male-biased genes (Sox11a, Dmrt1, Amh, Amhr2, Gsdf, Ar, Cyp17a2) likely play crucial roles in male sex differentiation and spermatogenesis, while female-biased genes (Foxl2, Cyp19a1a, Bmp15, Figla, Er) could be pivotal in ovarian differentiation and development. Numerous biological pathways linked to sex differentiation and gametogenesis were also identified. Additionally, E2 and T exhibited sexual dimorphism during sex differentiation and gonadal development. Based on these results, it is hypothesized that in C. maculata, the potential male sex differentiation pathway, Sox11a-Dmrt1-Sox9b, activates downstream sex-related genes (Amh, Amhr2, Gsdf, Ar, Cyp17a2) for testicular development, while the antagonistic pathway, Foxl2/Cyp19a1a, activates downstream sex-related genes (Bmp15, Figla, Er) for ovarian development. CONCLUSIONS: This study provides a comprehensive overview of gonadal dynamic changes during sex differentiation and gametogenesis in C. maculata, establishing a scientific foundation for sex control in this species.

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Blotched snakehead (Channa maculata) exhibits significant sexual dimorphism, as males display faster growth rates and larger body sizes compared to females. The cultivation of the all-male population of snakeheads holds substantial economic and ecological value. However, the mechanisms underlying sex determination and differentiation in C. maculata remain insufficiently elucidated. In this study, sexual dimorphism in growth became evident starting from 90 dpf through the measurement of body length and weight of male and female C. maculata at different developmental stages. Histological observations indicated that morphological sex differentiation in females and males occurred at 20­25 dpf or earlier and 30­35 dpf or earlier, respectively, corresponding to the appearance of the ovarian cavity or efferent duct anlage. Transcriptome analyses revealed divergent gene expression patterns in male and female gonads after 30 dpf, suggesting that the period preceding 30 dpf might be the critical time window for sex control in C. maculata. The periods of 40­60 dpf and 60­90 dpf marked the initiation of molecular sex differentiation in females and males, respectively. Male-biased genes (Sox11a, Dmrt1, Amh, Amhr2, Gsdf, Ar, Cyp17a2) likely play crucial roles in testicular differentiation and spermatogenesis, while female-biased genes (Foxl2, Cyp19a1a, Bmp15, Figla, Er) could be pivotal in ovarian differentiation and oogenesis. Additionally, numerous biological pathways linked to sex differentiation and gametogenesis were identified. Moreover, sexual dimorphism was observed in the levels of E₂ and T during gonadal differentiation and development. Based on these findings, it is hypothesized that in C. maculata, the potential male sex differentiation pathway, Sox11a­Dmrt1­Sox9b, activates downstream sex-related genes (Amh, Amhr2, Gsdf, Ar, Cyp17a2) for testicular development, while the antagonistic pathway, Foxl2/Cyp19a1a, activates downstream sex-related genes (Bmp15, Figla, Er) for ovarian development. This study provides a comprehensive overview of gonadal dynamic changes during sex differentiation and gametogenesis in C. maculata, thereby establishing a scientific foundation for sex control in this species.

Asunto(s)

Gametogénesis , Caracteres Sexuales , Diferenciación Sexual , Animales , Femenino , Masculino , Gónadas/crecimiento & desarrollo , Gónadas/anatomía & histología , Perfilación de la Expresión Génica , Peces/crecimiento & desarrollo , Peces/anatomía & histología , Peces/genética , Transcriptoma , Testículo/crecimiento & desarrollo , Testículo/anatomía & histología , Ovario/crecimiento & desarrollo , Ovario/anatomía & histología , Regulación del Desarrollo de la Expresión Génica , Channa punctatus

RESUMEN

BACKGROUND: Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT2AR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. METHODS: Male and female Sprague-Dawley rats (n = 25-29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2µg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a » log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q0 and α. RESULTS: Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT2AR activation decreased Q0 in female rats but increased Q0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. CONCLUSION: DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT2AR activation sex-dependently alters opioid reinforcement.

Asunto(s)

Anfetaminas , Fentanilo , Ratas Sprague-Dawley , Autoadministración , Animales , Masculino , Femenino , Fentanilo/farmacología , Ratas , Anfetaminas/farmacología , Caracteres Sexuales , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Relación Dosis-Respuesta a Droga , Analgésicos Opioides/farmacología , Alucinógenos/farmacología

RESUMEN

Differences in brain size between the sexes are consistently reported. However, the consequences of this anatomical difference on sex differences in intrinsic brain function remain unclear. In the current study, we investigate whether sex differences in intrinsic cortical functional organization may be associated with differences in cortical morphometry, namely different measures of brain size, microstructure, and the geodesic distance of connectivity profiles. For this, we compute a low dimensional representation of functional cortical organization, the sensory-association axis, and identify widespread sex differences. Contrary to our expectations, sex differences in functional organization do not appear to be systematically associated with differences in total surface area, microstructural organization, or geodesic distance, despite these morphometric properties being per se associated with functional organization and differing between sexes. Instead, functional sex differences in the sensory-association axis are associated with differences in functional connectivity profiles and network topology. Collectively, our findings suggest that sex differences in functional cortical organization extend beyond sex differences in cortical morphometry.

Asunto(s)

Corteza Cerebral , Imagen por Resonancia Magnética , Red Nerviosa , Caracteres Sexuales , Femenino , Masculino , Humanos , Corteza Cerebral/anatomía & histología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiología , Red Nerviosa/anatomía & histología , Red Nerviosa/fisiología , Red Nerviosa/diagnóstico por imagen , Adulto , Mapeo Encefálico/métodos , Adulto Joven , Encéfalo/anatomía & histología , Encéfalo/fisiología , Encéfalo/diagnóstico por imagen , Tamaño de los Órganos

RESUMEN

OBJECTIVE: To establish age and gender-specific paediatric and adult reference data for muscle function parameters assessed using Jumping Mechanography in the Indian population. METHODS: 2056 healthy individuals (1068 males), aged 5 to 60 years, performed 2 tests on a force platform (Leonardo Mechanograph, Novotec). Maximum power (Pmax) was assessed by single two legged jump and maximum force (Fmax) by multiple one legged hopping. LMS method was used to generate age and gender-specific reference curves for 5 - 20y group and mean ± SD and median ± IQR are presented for 21 - 60y group. RESULTS: In 5 - 20y group, Pmax and Fmax increased with age while in 21 - 60y group, the parameters declined with age. Females had lower Pmax values than males, consistently through all age groups. In children <15y, there were no intergender differences in Fmax, however, in further age groups, females had lower Fmax (p<0.001). Our participants showed lower Pmax and Fmax when compared with machine reference data based on German population (p<0.001). CONCLUSION: We present ethnicity-specific reference values for muscle function by Jumping Mechanography. These values are intended to help in clinical assessment of muscle function of Indian population and to identify those at risk of poor muscle function.

Asunto(s)

Músculo Esquelético , Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Adulto Joven , India , Músculo Esquelético/fisiología , Persona de Mediana Edad , Valores de Referencia , Preescolar , Fuerza Muscular/fisiología , Caracteres Sexuales , Miografía/métodos

RESUMEN

Introduction: Thyroid function during pregnancy fluctuates with gestational weeks, seasons and other factors. However, it is currently unknown whether there is a fetal sex-specific thyroid function in pregnant women. The purpose of this study was to investigate the fetal sex differences of maternal thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in pregnant women. Methods: This single-center retrospective real-world study was performed by reviewing the medical records of pregnant women who received regular antenatal health care and delivered liveborn infants in Shanghai First Maternity and Infant Hospital (Pudong branch), from Aug. 18, 2013 to Jul. 18, 2020. Quantile regression was used to evaluate the relationship between various variables and TSH and FT4 concentrations. The quantile regression also evaluated the sex impact of different gestational weeks on the median of TSH and FT4. Results: A total of 69,243 pregnant women with a mean age of 30.36 years were included. 36197 (52.28%) deliveries were boys. In the three different trimesters, the median levels (interquartile range) of TSH were 1.18 (0.66, 1.82) mIU/L and 1.39 (0.85, 2.05) mIU/L, 1.70 (1.19, 2.40) mIU/L; and the median levels (interquartile range) of FT4 were 16.63 (15.16, 18.31) pmol/L, 14.09 (12.30, 16.20) pmol/L and 13.40 (11.52, 14.71) pmol/L, respectively. The maternal TSH upper limit of reference ranges was decreased more in mothers with female fetuses during gestational weeks 7 to 12, while their FT4 upper limit of the reference ranges was increased more than those with male fetuses. After model adjustment, the median TSH level was 0.11 mIU/L lower (P <0.001), and FT4 level was 0.14 pmol/L higher (P <0.001) for mothers with female fetuses than those with male fetuses during gestational weeks 9 to 12. Discussion: We identified sexual dimorphism in maternal thyroid function parameters, especially during 9-12 weeks of pregnancy. Based on previous research, we speculated that it may be related to the higher HCG levels of mothers who were pregnant with girls during this period. However, longitudinal studies are needed to determine if fetal sex differences impact the maternal thyroid function across pregnancy.

Asunto(s)

Caracteres Sexuales , Pruebas de Función de la Tiroides , Glándula Tiroides , Tirotropina , Tiroxina , Humanos , Femenino , Embarazo , Estudios Retrospectivos , Adulto , Masculino , Tirotropina/sangre , Tiroxina/sangre , Glándula Tiroides/fisiología , Feto/fisiología , Edad Gestacional , China

RESUMEN

OBJECTIVE: The aim of the present review was to highlight gender and sex differences in spondyloarthritis (SpA) to achieve a better awareness of the unmet needs of women with SpA. METHODS: A literature search of PubMed was performed, including manuscripts in English published in the last twenty years, to select and analyze articles related to SpA and sex and gender differences in epidemiology, genetics, immunology, clinical features, and response to treatment. RESULTS: Women and men with SpA have different disease phenotypes, and this heterogeneity mirrors anatomical, physiological, and hormonal differences, as well as peculiar variability in response to treatment. These underestimated differences, which include several biological factors and intertwined social factors, contribute to diagnostic delay and increased disease burden in women with SpA. CONCLUSIONS: This review elucidates gender differences in SpA and raises awareness about the need for gender-related stratification of SpA patients with the concomitant implementation of SpA gender differences in future research and upcoming clinical trials. A deeper knowledge of SpA in women is indispensable to pave the way for real personalized medicine for SpA patients to reduce misdiagnosis and delay in intercepting the disease.

Asunto(s)

Espondiloartritis , Humanos , Femenino , Espondiloartritis/diagnóstico , Espondiloartritis/etiología , Factores Sexuales , Masculino , Fenotipo , Diagnóstico Tardío , Caracteres Sexuales

RESUMEN

OBJECTIVE: Spondyloarthritis is a family of inflammatory diseases subdivided into those affecting the spine, called axial spondyloarthritis, and those involving peripheral joints, such as psoriatic arthritis (PsA). Several studies have reported differences in clinical manifestations, outcomes, and treatment responses between male and female PsA patients. The aim of our review was to evaluate if differences may also be identified in the context of cardiovascular (CV) risk factors and diseases. METHODS: Patients with PsA have a higher CV risk than the general population. The increased CV risk associated with PsA is likely caused by the complex interplay of traditional CV risk factors, chronic systemic inflammation, and side effects related to the use of certain anti-rheumatic drugs. RESULTS: Sex differences in CV risk factors in PsA patients, according to several studies, are controversial. However, the few studies that reported sex-stratified estimates did not find differences in the risk of stroke and myocardial infarction between sexes. The same also holds true for CV mortality. These mixed results may be related to the different study designs and case definitions, as well as genetic and geographical variability across the investigated populations. CONCLUSIONS: In conclusion, our review suggests that the evaluation of sex-gender aspects of CV comorbidities in PsA should be a central step in the context of personalized medicine in order to prevent and treat properly associated comorbidities.

Asunto(s)

Artritis Psoriásica , Enfermedades Cardiovasculares , Comorbilidad , Humanos , Artritis Psoriásica/epidemiología , Femenino , Masculino , Factores Sexuales , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Espondiloartritis/epidemiología , Espondiloartritis/complicaciones , Factores de Riesgo , Caracteres Sexuales , Factores de Riesgo de Enfermedad Cardiaca , Antirreumáticos/uso terapéutico

RESUMEN

Sex and gender differences play a crucial role in health and disease outcomes. This study used data from the National Health and Nutrition Examination Survey to explore how environmental exposures affect health-related traits differently in males and females. We utilized a sex-stratified phenomic environment-wide association study (PheEWAS), which allowed the identification of associations across a wide range of phenotypes and environmental exposures. We examined associations between 272 environmental exposures, including smoking-related exposures such as cotinine levels and smoking habits, and 58 clinically relevant blood phenotypes, such as serum albumin and homocysteine levels. Our analysis identified 119 sex-specific associations. For example, smoking-related exposures had a stronger impact on increasing homocysteine, hemoglobin, and hematocrit levels in females while reducing serum albumin and bilirubin levels and increasing c-reactive protein levels more significantly in males. These findings suggest mechanisms by which smoking exposure may pose higher cardiovascular risks and greater induced hypoxia for women, and greater inflammatory and immune responses in men. The results highlight the importance of considering sex differences in biomedical research. Understanding these differences can help develop more personalized and effective health interventions and improve clinical outcomes for both men and women.

Asunto(s)

Exposición a Riesgos Ambientales , Humanos , Femenino , Masculino , Exposición a Riesgos Ambientales/efectos adversos , Persona de Mediana Edad , Adulto , Factores Sexuales , Fumar/efectos adversos , Encuestas Nutricionales , Fenotipo , Caracteres Sexuales , Cotinina/sangre

RESUMEN

Transcription enhancers are genomic sequences regulating common and tissue-specific genes and their disruption can contribute to human disease development and progression. Klotho, a sexually dimorphic gene specifically expressed in kidney, is well-linked to kidney dysfunction and its deletion from the mouse genome leads to premature aging and death. However, the sexually dimorphic regulation of Klotho is not understood. Here, we characterize two candidate Klotho enhancers using H3K27ac epigenetic marks and transcription factor binding and investigate their functions, individually and combined, through CRISPR-Cas9 genome engineering. We discovered that only the distal (E1), but not the proximal (E2) candidate region constitutes a functional enhancer, with the double deletion not causing Klotho expression to further decrease. E1 activity is dependent on HNF1b transcription factor binding site within the enhancer. Further, E1 controls the sexual dimorphism of Klotho as evidenced by qPCR and RNA-seq. Despite the sharp reduction of Klotho mRNA, unlike germline Klotho knockouts, mutant mice present normal phenotype, including weight, lifespan, and serum biochemistry. Lastly, only males lacking E1 display more prominent acute, but not chronic kidney injury responses, indicating a remarkable range of potential adaptation to isolated Klotho loss, especially in female E1 knockouts, retaining renoprotection despite over 80% Klotho reduction.

Asunto(s)

Elementos de Facilitación Genéticos , Glucuronidasa , Factor Nuclear 1-beta del Hepatocito , Riñón , Proteínas Klotho , Caracteres Sexuales , Animales , Proteínas Klotho/metabolismo , Ratones , Masculino , Femenino , Riñón/metabolismo , Glucuronidasa/genética , Glucuronidasa/metabolismo , Factor Nuclear 1-beta del Hepatocito/genética , Factor Nuclear 1-beta del Hepatocito/metabolismo , Ratones Noqueados , Regulación de la Expresión Génica , Ratones Endogámicos C57BL

RESUMEN

BACKGROUND: Sex differences exist in the prevalence and progression of major glomerular diseases. Podocytes are the essential cell-type in the kidney which maintain the physiological blood-urine barrier, and pathological changes in podocyte homeostasis are critical accelerators of impairment of kidney function. However, sex-specific molecular signatures of podocytes under physiological and stress conditions remain unknown. This work aimed at identifying sexual dimorphic molecular signatures of podocytes under physiological condition and pharmacologically challenged homeostasis with mechanistic target of rapamycin (mTOR) inhibition. mTOR is a crucial regulator involved in a variety of physiological and pathological stress responses in the kidney and inhibition of this pathway may therefore serve as a general stress challenger to get fundamental insights into sex differences in podocytes. METHODS: The genomic ROSAmT/mG-NPHS2 Cre mouse model was used which allows obtaining highly pure podocyte fractions for cell-specific molecular analyses, and vehicle or pharmacologic treatment with the mTOR inhibitor rapamycin was performed for 3 weeks. Subsequently, deep RNA sequencing and proteomics were performed of the isolated podocytes to identify intrinsic sex differences. Studies were supplemented with metabolomics from kidney cortex tissues. RESULTS: Although kidney function and morphology remained normal in all experimental groups, RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways. Interestingly, rapamycin abolished prominent sex-specific clustering of podocyte gene expression and induced major changes only in male transcriptome. Several sex-biased transcription factors could be identified as possible upstream regulators of these sexually dimorphic responses. Concordant to transcriptomics, metabolomic changes were more prominent in males. Remarkably, high number of previously reported kidney disease genes showed intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition. CONCLUSIONS: Our results highlight remarkable intrinsic sex-differences and sex-specific response patterns towards pharmacological challenged podocyte homeostasis which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. This work provides rationale and an in-depth database for novel targets to be tested in specific kidney disease models to advance with sex-specific treatment strategies.

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The global burden of chronic kidney diseases is rapidly increasing and is projected to become the fifth most common cause of years of life lost worldwide by 2040. Sexual dimorphism in kidney diseases and transplantation is well known, yet sex-specific therapeutic strategies are still missing. One reason is the lack of knowledge due to the lack of inclusion of sex as a biological variable in study designs. This work aimed at identification of molecular signatures of male and female podocytes, gate-keepers of the glomerular filtration barrier. Like cardiomyocytes, podocytes are terminally differentiated cells which are highly susceptible towards pathological challenges. Podocytes are the decisive cell-type of the kidney to maintain the physiological blood-urine barrier, and disturbances of their homeostasis critically accelerate kidney function impairment. By help of a genomic mouse model, highly purified podocytes were obtained from male and female mice with and without pharmacological challenge of the mechanistic target of rapamycin (mTOR) signaling pathway which is known to be deregulated in major kidney diseases. Deep RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. Remarkably, high number of previously reported kidney disease genes showed so far unknown intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition. Our work provides an in-depth database for novel targets to be tested in kidney disease models to advance with sex-specific treatment strategies.

Asunto(s)

Homeostasis , Podocitos , Caracteres Sexuales , Sirolimus , Animales , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Masculino , Femenino , Sirolimus/farmacología , Homeostasis/efectos de los fármacos , Ratones , Serina-Treonina Quinasas TOR/metabolismo , Transcriptoma , Inhibidores mTOR/farmacología

RESUMEN

Cell identities are defined by intrinsic transcriptional networks and spatio-temporal environmental factors. Here, we explored multiple factors that contribute to the identity of adipose stem cells, including anatomic location, microvascular neighborhood, and sex. Our data suggest that adipose stem cells serve a dual role as adipocyte precursors and fibroblast-like cells that shape the adipose tissue's extracellular matrix in an organotypic manner. We further find that adipose stem cells display sexual dimorphism regarding genes involved in estrogen signaling, homeobox transcription factor expression and the renin-angiotensin-aldosterone system. These differences could be attributed to sex hormone effects, developmental origin, or both. Finally, our data demonstrate that adipose stem cells are distinct from mural cells, and that the state of commitment to adipogenic differentiation is linked to their anatomic position in the microvascular niche. Our work supports the importance of sex and microvascular function in adipose tissue physiology.

Asunto(s)

Adipocitos , Tejido Adiposo , Fibroblastos , Caracteres Sexuales , Células Madre , Animales , Femenino , Adipocitos/citología , Adipocitos/metabolismo , Masculino , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Fibroblastos/metabolismo , Fibroblastos/citología , Células Madre/metabolismo , Células Madre/citología , Ratones , Diferenciación Celular , Adipogénesis/genética , Ratones Endogámicos C57BL , Matriz Extracelular/metabolismo , Humanos

RESUMEN

Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure. This Review provides an overview of the impact of the way hypertension research has explored sex as a biological variable (SABV). Emphasis is placed on epidemiological studies, hypertension clinical trials, the genetics of hypertension, sex differences in immunology and gut microbiota in hypertension, and the effect of sex on the central control of blood pressure. The goal is to offer historical perspective on SABV in hypertension, highlight recent studies that include SABV, and identify key gaps in SABV inclusion and questions that remain in the field. Through continued awareness campaigns and engagement/education at the level of funding agencies, individual investigators, and in the editorial peer review system, investigation of SABV in the field of hypertension research will ultimately lead to improved clinical outcomes.

Asunto(s)

Hipertensión , Humanos , Hipertensión/epidemiología , Femenino , Masculino , Caracteres Sexuales , Presión Sanguínea , Microbioma Gastrointestinal , Investigación Biomédica , Factores Sexuales

RESUMEN

Testosterone (T) and 17ß-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, antiinflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T's conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.

Asunto(s)

Estradiol , Testosterona , Humanos , Testosterona/metabolismo , Masculino , Femenino , Estradiol/metabolismo , Resistencia a la Insulina , Caracteres Sexuales , Envejecimiento/metabolismo , Músculo Esquelético/metabolismo , Animales