Changes In Steroids Research Articles

Thyroid hormones in female and male reproduction with special reference to dogs and cats

Thyroid hormones have an important function in numerous physiological processes in humans and animals, including the regulation of metabolism, growth and development of individual and reproductive function. The thyroid hormones, triiodothyronine (T3) and thyroxine (T4), have a direct effect on the reproductive organs and an indirect effect in interaction with other hormones. Thyroid hormones influence the reproductive system by regulating metabolism and tissue development of the ovaries, uterus and placenta. Changes in the serum concentrations of T3 and T4 lead to disturbances in overall body function. Thyroid dysfunction, including hypothyroidism and hyperthyroidism, can lead to significant reproductive problems. The aim of this review was to describe the functions of thyroid hormones and the effects of hypothyroidism and hyperthyroidism on the animal reproductive system. Hypothyroidism is often caused by autoimmune diseases such as lymphocytic thyroiditis, and is associated with later puberty, reduced fertility and abnormalities in reproductive organ development. Hypothyroidism can lead to a prolonged interval, absent cycles, silent oestrus cycles, prolonged oestrus bleeding, and a lack of libido, with the occurrence of infertility, miscarriages, stillbirths and mummified foetuses. In males, hypothyroidism leads to a decrease in libido, semen quality, ejaculate volume, testicular atrophy, hypospermia and azoospermia. Hyperthyroidism, on the other hand, is usually the result of thyroid cancer, which produces excessive amounts of thyroid hormones. Increased concentrations of thyroid hormones lead to disturbances in the physiological balance of reproductive hormones, irregular oestrus cycles, anovulation and reduced fertility, as well as a decrease in the weight of the ovaries and the number of healthy follicles, with a simultaneous increase in the number of atretting follicles. The effects of hyperthyroidism on male fertility include disorders of spermatogenesis, changes in sex hormone levels and changes in sperm quality, such as hypospermia, oligozoospermia, asthenozoospermia and teratozoospermia. It is important to diagnose and treat thyroid disorders in time in order to prevent negative effects on fertility and reproduction in animals.

Luteinizing hormone is independently associated with high-sensitive cardiac troponin T elevation in postmenopausal T2DM patients: A cross-sectional study.

It is known that the risk of ischemic heart disease increases in patients with type 2 diabetes mellitus (T2DM). For female patients, the incidence of heart disease can be even greater after menopause, accompanied by dramatic changes in sex hormones. We investigated the correlations between sex hormones and markers of ischemic heart diseases in postmenopausal females with T2DM patients. This cross-sectional study collected data from 324 hospitalized postmenopausal females with T2DM. Multiple linear regression analyses were conducted to determine the correlations between sex hormones and cardiac markers including high-sensitive cardiac troponin T (hs-cTnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels. Multiple linear regression analyses revealed that luteinizing hormone (LH) was positively and independently associated with hs-cTnT concentrations in postmenopausal females with T2DM (β = 0.189, p = 0.002). Postmenopausal females with T2DM and subclinical myocardial injury had higher LH levels than those without subclinical myocardial injury (29.67 vs. 25.08 mIU/mL, p < 0.001). A multivariate logistic regression analysis confirmed an independent and significant association between elevated LH and subclinical myocardial injury in postmenopausal females with T2DM (adjusted odds ratio [OR] = 1.077, 95% confidence interval [CI], 1.033-1.124; p < 0.001). As another gonadotropin, the follicle-stimulating hormone did not show independent correlations with hs-cTnT or NT-proBNP (p > 0.05). Neither estrogen nor testosterone was correlated with cardiac markers. Elevated LH levels were positively and independently associated with increased hs-cTnT levels in postmenopausal women with T2DM. Our findings suggest that LH could serve as a potential marker for assessing the risk of subclinical myocardial injury in postmenopausal females with T2DM.

N-acetylcysteine and zinc sulphate abate di-2-ethylhexyl phthalate-mediated reproductive dysfunction in rats: Focus on oxidative and sex hormone receptors mechanisms

Objective: To investigate the potential of N-acetylcysteine (NAC) and zinc sulphate (ZnSO4) in mitigating reproductive dysfunction caused by di-2-ethylhexyl phthalate (DEHP) in rats and to understand the underlying mechanisms, specifically oxidative stress and sex hormone receptor activity. Methods: Thirty-five male Wistar rats were randomly divided into five equal groups (n=7 per group). Group 1 was administered 0.5 mL of distilled water and served as the control group. Group 2 was given only DEHP (750 mg/kg/day), while group 3, 4 and 5 were given DEHP (750 mg/kg/day) plus NAC (100 mg/kg/day), DEHP (750 mg/kg/day) plus ZnSO4 (0.5 mg/kg/day), and DEHP (750 mg/kg/day) plus NAC (100 mg/kg/day) as well as ZnSO4 (0.5 mg/kg/day), respectively. All treatments lasted for 21 days. Samples were obtained after the rats were sacrificed, and hormones levels in the serum and markers of oxidative stress in the testicles were analyzed using the enzyme-linked immunosorbent assay. The amount of androgen receptors in the testicles was determined by immunohistochemistry, and the susceptibility of testosterone and DEHP to bind to androgen receptor and 5α-reductase was determined by molecular docking studies. Results: DEHP decreased reproductive hormones, testicular antioxidant enzymes, increased malondialdehyde levels, and negatively impacted histology of the pituitary and testes. NAC or ZnSO4 treatment showed a marked improvement in testicular antioxidant status and hormone levels, as well as a positive effect on the histology of the pituitary and testes. The combination of both treatments appeared to be more effective. The affinity of DEHP to bind to androgen receptors may lead to disruption of androgen receptor signaling, which can further result in dysfunction of hormones related to androgen. However, NAC is more likely to form stronger binding interactions with follicle stimulating hormone and luteinizing hormone receptors, as well as gonadotropin-releasing hormone receptors, when compared to DEHP. Conclusions: The possibility that NAC and ZnSO4 could downregulate DEHP-induced sex hormone changes is suggested by their potential to reduce toxicity.

Advances in the Effects of Heat Stress on Ovarian Granulosa Cells: Unveiling Novel Ferroptosis Pathways.

Heat stress has been one of the key research areas for researchers due to the wide-ranging effects and complex mechanisms of action of its stress product reactive oxygen species (ROS). The aim of this paper is to comprehensively review and summarize the effects of heat stress on ovarian granulosa cells and their mechanism of action. We systematically reviewed the effects of heat stress on ovarian granulosa cells, including intracellular steroid hormone changes, oxidative stress, apoptosis, and mitochondrial function. Meanwhile, this paper discusses in detail several major mechanisms by which heat stress induces apoptosis in ovarian granulosa cells, such as through the activation of apoptosis-related genes, induction of endoplasmic reticulum stress, and the mitochondrial pathway. In addition, we analyzed the mechanism of ferroptosis in ovarian granulosa cells under heat stress conditions, summarized the potential association between heat stress and ferroptosis in light of the existing literature, and explored the key factors in the mechanism of action of heat stress, such as the signaling pathways of Nrf2/Keap1, HSPs, and JNK, and analyzed their possible roles in the process of ferroptosis. Finally, this paper provides an outlook on the future research direction, describing the possible interaction between heat stress and ferroptosis, with a view to providing a theoretical basis for further understanding and revealing the complex mechanism of ferroptosis occurrence in ovarian granulosa cells under heat stress.

A prediction model for gestational diabetes mellitus based on steroid hormonal changes in early and mid-down syndrome screening: A multicenter longitudinal study

BackgroundSteroid hormones (SH) during pregnancy are associated with the development of gestational diabetes mellitus (GDM). Early and mid-Down syndrome screening is used to assess the risk of Down syndrome in the fetus. It is unclear whether changes in SH during this period can be used as an early predictor of GDM. MethodsThis study was a multicenter, longitudinal cohort study. GDM is diagnosed by an oral glucose tolerance test (OGTT) between 24 and 28 weeks of gestation. We measured SH levels at early and mid-Down syndrome screening, respectively. Based on the SH changes, logistic regression analysis was used to construct a prediction model for GDM. Finally, evaluated the model’s predictive performance by creating a receiver operating characteristic curve (ROC) and performing external validation. ResultsThis study enrolled 193 pregnant women (discovery cohort, n = 157; validation cohort, n = 36). SH changes occur dynamically after pregnancy. At early Down syndrome screening, only cortisol (F) (p < 0.05, 95 % CI 4780.95–46083.68) was elevated in GDM. At mid-Down syndrome screening, free testosterone (FT) (p < 0.01, 95 % CI 0.10–0.55) and estradiol (E2) (p < 0.05, 95 % CI 203.55–1784.78) were also significantly elevated. There were significant differences in the rates of change in E2 (Fold change (FC) = 1.3425, p = 0.0072), albumin (ALB) (FC=1.5759, p = 0.0117), and dihydrotestosterone (DHT) (FC=-2.1234, p = 0.0165) between GDM and no-GDM. Stepwise logistic regression analysis resulted in the best predictive model, including six variables (Δweight, ΔF, Δcortisone (E), ΔE2, Δprogesterone (P), ΔDHT). The area under the curve for this model was 0.791, and for the external validation cohort, it was 0.799. ConclusionsA GDM prediction model can be constructed using SH measures during early and mid-Down syndrome screening.

Investigating the influence of estrous cycle-dependent hormonal changes on neurogenesis in adult mice

ObjectiveNeurogenesis is the process of generating new neurons from neural stem cells (NSCs) in the adult brain. Sex hormones play an essential role in the development of the brain. The aim of this study was to evaluate the neurogenic changes in the brain at different phases of the estrous cycle in adult mice. Materials and methodsFemale NMRI mice were divided into four groups: 1- Estrous, 2- Proestrous, 3- Metestrous, and 4- Diestrous. Different stages of the estrous cycle were determined by staining of vaginal smears. The level of estrogen, progesterone, prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) hormones was evaluated by the enzyme-linked immunosorbent assay (ELISA) method. The expression of brain-derived neurotrophic factor) BDNF), nerve growth factor (NGF), ciliary neurotrophic factor(CNTF)) genes in hippocampal and the expression of glial fibrillary acidic protein (GFAP) in subventricular zone (SVZ) tissue were evaluated. ResultsThe serum estrogen and FSH increased significantly in Proestrous group (p < 0.001). Also, progesterone and prolactin hormones were significantly increased in the Diaestrus group (p < 0.001). The expression levels of BDNF, NGF, and CNTF significantly increased in the hippocampal tissue of Proestrous and Diaestrus groups (p < 0.001). The number of GFAP+ cells in SVZ of the Proestrous and Diestrous groups had a significant increase (p < 0.05, p < 0.01, p < 0.001). ConclusionOur data showed that Changes in sex hormones, especially estrogen in the estrous cycle, can cause the production of new neurons and astrocytes in the hippocampus and SVZ. Therefore, the increase in neurotrophic factors in the Proestrus and Diestrus leads to neurogenesis in adult mice brains.

Weight Loss Differentially Impacts Sex Hormones in Women and Men with Type 2 Diabetes: Look AHEAD Sex Hormone Study.

Despite sex differences in T2D, few studies have examined the role of sex hormones. We sought to assess the impact of weight loss, the cornerstone of T2D management, on sex hormone levels. This was an ancillary study to the Look AHEAD (Action for Health In Diabetes) Study (n=850 postmenopausal females, n=890 males, with T2D and BMI ≥25 kg/m2). We measured total testosterone (T), estradiol (E2) and sex hormone binding globulin (SHBG) and calculated bioavailable T (bioT). We examined the effect of the intensive lifestyle intervention (ILI) on hormone changes, whether changes were mediated by waist circumference and sex differences in treatment effect. The baseline mean age was 60 years with a higher proportion of Black females (21%) vs. males (9%) and higher mean BMI in females vs. males (36.3 vs. 34.8 kg/m2). At year 1 in females, ILI decreased E2 by 15% and bioT by 13% and increased SHBG by 21%. At year 1 in males, ILI did not change E2 levels, but increased T by 14% and increased SHBG by 18%. The effect was attenuated over 4 years, there were statistically significant sex differences in treatment effect and change in waist circumference due to ILI at year 1 was a significant mediator of sex hormone changes. Weight loss in T2D resulted in sex hormone changes, which varied by sex and were mediated by changes in WC. Changes in sex hormone due to weight loss in T2D should be considered in the context of an individual's health risks, including cardiovascular, bone health, menopausal symptoms and cognition.

Adolescent exposure to a mixture of per- and polyfluoroalkyl substances (PFAS) depletes the ovarian reserve, increases ovarian fibrosis, and alters the Hippo pathway in adult female mice.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals known for their environmental persistence and resistance to biodegradation. This study investigated the impact of adolescent exposure to a PFAS mixture on adult ovarian function. Female CD-1 mice were orally exposed to vehicle control or a PFAS mixture (comprised of perfluorooctanoic acid, perfluorooctanesulfonic acid, undecafluoro-2-methyl-3-oxahexanoic acid, and perfluorobutanesulfonic acid) for 15 d. After a 42-d recovery period, reproductive hormones, ovarian fibrosis, and ovarian gene and protein expression were analyzed using ELISA, Picrosirius red staining, qPCR, and immunoblotting, respectively. Results revealed that PFAS exposure did not affect adult body or organ weight, although ovarian weight slightly decreased. PFAS-exposed mice exhibited a disturbed estrous cycle, with less time spent in proestrus than control mice. Follicle counting indicated a reduction in primordial and primary follicles. Serum analysis revealed no changes in steroid hormones, follicle-stimulating hormone, or anti-Müllerian hormone, but a significant increase in luteinizing hormone was observed in PFAS-treated mice. Ovaries collected from PFAS-treated mice had increased mRNA transcripts for steroidogenic enzymes and fatty acid synthesis-related genes. PFAS exposure also increased collagen content in the ovary. Additionally, serum tumor necrosis factor-α levels were higher in PFAS-treated mice. Finally, transcripts and protein abundance for Hippo pathway components were upregulated in the ovaries of the PFAS-treated mice. Overall, these findings suggest that adolescent exposure to PFAS can disrupt ovarian function in adulthood.

Mediating effect of menopausal symptoms between the lifestyle and depressive symptoms.

This study aimed to explore relationship between lifestyle and depressive symptoms and evaluated the mediating effect of menopausal symptoms. This was a secondary analysis of a survey in Hunan Province, China. We selected 3190 women aged 40 to 55 into final analyses. Menopausal and depressive symptoms were assessed by the Kupperman Menopausal Index and the 9-item Patient Health Questionnaire, respectively. A self-administered questionnaire was used to collect demographic and lifestyle information. The prevalence of depressive symptoms was 19.5%. After adjusting for demographic variables, passive smoking, drinking, and intensity of physical activity were positively associated with depressive symptoms. Frequency of exercise was a protective factor for depressive symptoms (AOR = 0.783, 95%CI: 0.446-0.991). Excess or restricted sleep duration was associated with higher probability of having depressive symptoms (AOR = 1.746, 95% CI: 1.324-2.304). Menopausal symptoms partially mediated the relationship between lifestyle and depressive symptoms. Findings highlighted the importance of menopausal symptoms in the relationship between the lifestyle and depressive symptoms, and provided a possibility that active lifestyle might improve depression symptoms among women at perimenopause through changes in sex hormones.

Morphology, Glycan Pattern, Heat Shock Proteins, and Sex Steroid Receptors Expression in the Tubal Fimbria Epithelium of the Baboon Papio hamadryas during the Menstrual Cycle.

The oviductal fimbria is the first extraovarian anatomical structure that the cumulus-oocyte complex (COC) encounters, and is sensitive to sex hormone changes. The morphology, glycan pattern, expression of heat shock proteins (HSPs), estradiol receptor (ER), and progesterone receptor (PR) were investigated in the oviductal fimbria epithelium of the baboon (Papio hamadryas) during the menstrual cycle. The morphology was investigated by light and scanning electron microscopy; the glycopattern was characterized using conventional and lectin histochemistry; HSPs (60, -70, -90), ER, and PR were localized immunohistochemically. Well-differentiated ciliated and nonciliated cells were present only during the preovulatory phase. The nonciliated cells contained small apical protrusions and thin microvilli. During the preovulatory phase (1) the luminal surface of the fimbria displayed acidic glycans, complex N-glycans containing fucose, and oligolactosamine residues; (2) nonciliated cells expressed HSP60 and HSP90 in the apical blebs, HSP70 in the nucleus and cytoplasm, as well as nuclear ERα and PR; (3) ciliated cells showed HSP70 in the nucleus, cytoplasm, and cilia that also expressed HSP90 and PR. These results are related to the function of the fimbria where the early COC-oviduct crosstalk occurs and may represent a benchmark for translational studies of other primates.

Sex hormone trajectories and association to outcomes after out-of-hospital cardiac arrest

BackgroundOutcomes and susceptibility to out-of-hospital cardiac arrest (OHCA) are known to differ by sex, yet little is known about changes in sex hormones after OHCA. We sought to determine the trajectory of sex hormones after OHCA and their association to survival and neurological outcome. MethodsPlasma samples were collected from those that survived to hospital admission at four time points (1, 6, 24, and 48 h) and estrone, estradiol, progesterone, and testosterone concentrations were quantified via liquid chromatography-mass spectrometry. Trends in hormones were plotted over time by sex and outcomes. The association between sex, hormone levels with survival and neurological outcome (cerebral performance category 1–2 indicating good outcome and 3–5 for poor outcome) were determined using generalized estimating equation models. ResultsOf the 94 OHCA patients, 50 were males and 44 females, with a mean age of 61.3 (+15.7) years. Despite older age and lower BCPR in females compared to males, females had higher proportion of good neurological outcome compared to males. Over the 48 h, estrone increased, testosterone decreased, and estradiol and progesterone remained flat. Survivors had lower levels of estrone at all time points but only at early time points for estradiol, progesterone and testosterone. Lower estrone level predicted survival at discharge, even after adjusting for time, sex, age, and hormones independently (β = −3.38, 95% CI = −5.71, −0.85). Females had better neurological scores compared to males after adjusting for estrone (β = 1.27, 95% CI = 0.01, 2.53) and estradiol (β = 2.92, 95% CI = 1.13, 4.70). ConclusionsSurvivors and those with favorable neurological outcome had lower trend in estrone. The sex hormone estrone, present in both males and females, may be a predictor of survival. When adjusted for estrogens, female sex had better neurological recovery compared to males. The difference in neurological outcome by sex is not explained by estrogens. However, these finding open the door for exploration of other sex-specific pathways in resuscitation after OHCA.

Sex-differential testosterone response to long-term weight loss

ObjectivesObesity-associated gonadal dysfunction is a common comorbidity in patients seeking weight loss interventions. We examined the incremental effect of weight loss on gonadal axes in men and women over 3 years. Changes in sex hormones were compared between dietary intervention (Diet) and bariatric procedures: Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and laparoscopic adjustable gastric banding (LAGB). Additional analysis assessed changes in corticotropic, somatotropic and thyroid axes after weight loss interventions.MethodsThis prospective, observational study included 61 adults with Body Mass Index >30 kg/m2, mean age 51 (SD = 11) years. Endocrine parameters were measured at baseline and at 6 timepoints over 36-months.ResultsFor each 1 kg of weight lost, between baseline and 36 months, total testosterone increased by 0.6% (95% CI: 0.2%, 1.0%, p = 0.002) in males and decreased by 0.8% (95% CI: −1.4%, −0.3%, p = 0.003) in females. These changes remained statistically significant when controlled for age and for menopausal status in females. At 36 months, in comparison with Diet, RYGB women had lower total testosterone by 54% (95% CI: −90%, −17%, p = 0.004), reduced free androgen index (FAI) by 65% (95% CI; −114%, −17%, p = 0.009) while SG had reduced FAI by 39% (95% CI; −77%, 0%, p = 0.05). No such differences between groups were noted for male subjects. Adrenocorticotropic hormone declined by 0.3% (95% CI: 0.0, −0.5%, p = 0.05), insulin-like growth factor-1 increased by 0.4% (95% CI; 0.2%, 0.7%, p = 0.005), without such thyrotrophin change for each 1 kg of weight loss, for entire cohort, over 36 months.ConclusionsThe testosterone changes observed in this study were proportional to the amount of weight loss. In females, reduction in androgens was independent of age and menopausal status and more pronounced after bariatric procedures. This study finding warrants further clinical research to explore an impact of androgen reduction on functional and cognitive status in postmenopausal women. The observed changes in pituitary hormones may contribute to the metabolic benefits of bariatric surgery.

Delirium in Neurocritical Care: Uncovering Undisclosed Psychotropic Substance and Medication Use and Stress Exposure by Hair Analysis.

In intensive care, delirium is frequent, prolongs the stay, increases health care costs, and worsens patient outcome. Several substances and medications as well as stress can impact the risk of delirium; however, assessment of previous exposure to psychotropic agents and stress by self-reports or third-party information is not always reliable. Hair analysis can be used to objectively assess medication and substance use (including chronic alcohol consumption), and allows for the determination of stress-related long-term changes in steroid hormones and endocannabinoids. Consecutive adult patients with acute brain injury admitted to the neurocritical care unit were included. Delirium was diagnosed using the Confusion Assessment Method for the Intensive Care Unit. Liquid chromatography coupled with tandem mass spectrometry was used to investigate psychoactive substances and medications, ethyl glucuronide, steroid hormones, and endocannabinoids in hair samples. Univariable and multivariable analyses were used to reveal any associations with the occurrence of delirium. Of 50 consecutive patients, 21 (42%) were diagnosed with delirium. Detection of antipsychotics or antidepressants in hair was more frequent in patients with delirium (antidepressants: 43% vs. 14%, p = 0.040; antipsychotics: 29% vs. 0%, p = 0.021). These patients also displayed higher ethyl glucuronide levels (p = 0.049). Anandamide (AEA) concentrations were higher in patients with delirium (p = 0.005), whereas oleoylethanolamide (p = 0.045) and palmitoylethanolamide (PEA) (p = 0.017) concentrations were lower in patients with delirium. Backward stepwise logistic regression analysis revealed antidepressants and AEA/PEA to be independent relevant predictors of delirium. Hair analysis provides crucial and otherwise unattainable information regarding chronic stress and the use of psychotropic substances and medications. Undisclosed antidepressant/antipsychotic use or intense chronic alcohol consumption is susceptible to treatment (continuation of medication or provision of low-dose benzodiazepines in case of alcohol). Chronic stress can be evaluated using stress markers and endocannabinoids in hair, potentially allowing for personalized delirium risk stratification and preventive measures.

Bushen Zhuyun Decoction Improves Endometrial Receptivity by Inhibiting NF-κB/NLRP3 Signaling Pathway.

Bushen Zhuyun Decoction (BSZY), a traditional Chinese herbal prescription has shown promising effects on gynecological infertility, but the mechanism for endometrial receptivity is still unclear. This study aimed to investigate the regulatory effects of BSZY on endometrial receptivity, which plays a key role in colonization of embryo, and its regulatory mechanisms associated with NF- κB/NLRP3 pathway. SD rats at reproductive age with affected endometrial receptivity was established using mifepristone (RU486), and the regulatory effects of BSZY on endometrial receptivity were evaluated by H&E staining, and changes in sex hormones by ELISA and Western blot. Moreover, human endometrial RL95-2 cells were treated with H2O2, and inflammatory cytokines in rats and RL95-2 cells were analyzed by ELISA. The activation of NF-κB/NLRP3 signaling pathway in RL95-2 cells were characterized using immunofluorescence and Western blot. Mitochondrial morphology and function in RL95-2 cells were observed by transmission electron microscope and cell mitochondrial stress test. BSZY increased uterine endometrial thickness and attenuate histopathological changes induced by RU486. BSZY can regulate endometrial estrogen receptor and progesterone receptor, and the levels of sex hormones and inflammatory cytokines in pregnant rats. BSZY-containing serum also showed strong anti-inflammatory and cytoprotective effects in vitro. In addition, BSZY-containing serum inhibited the activation of NF-κB/NLRP3 signaling pathway, and improve mitochondrial morphology and function in RL95-2 cells. BSZY can improve endometrial receptivity, potentially by improving mitochondrial morphology and function to inhibit the activation of NF-κB/NLRP3 signaling pathway in endometrial cells, thus regulate inflammation to improve endometrial receptivity.

Sex differences in CGRP-induced vasodilation of human middle meningeal arteries but not human coronary arteries: implications for migraine.

Migraine prevalence and levels of calcitonin gene-related peptide (CGRP), a peptide involved in migraine pathophysiology, differ between men and women, and appear to be affected by changes in sex hormones. The present study investigated the sex-specific responses to CGRP in human isolated arteries. CGRP-induced relaxation of 62 (28 men and 34 women) human isolated middle meningeal arteries (HMMA) and 139 (69 men and 70 women) human isolated coronary arteries (HCA) was compared between men and women in groups <50 years and ≥50 years of age as a proxy for pre- and postmenopausal status in women, as well as matched-age groups for men. In HCA, no differences were observed between male and female tissue, or between the different age groups. However, in HMMA, the maximum response was significantly smaller and CGRP was less potent in females <50 compared with males <50 years of age. No differences were observed between the older age groups. Sex differences were observed for CGRP-induced relaxation of HMMA, but not HCA. These differences could arise from differential receptor expression in the vascular beds combined with the effect of sex hormones on CGRP and subsequent receptor desensitization.

Chronic Administration of Cannabinoid Agonists ACEA, AM1241, and CP55,940 Induce Sex-Specific Differences in Tolerance and Sex Hormone Changes in a Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB1)-selective, cannabinoid receptor type 2 (CB2)-selective, and CB1/CB2 mixed agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. SIGNIFICANCE STATEMENT: CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Human chorionic gonadotropin regulates cytokine production by lymphocytes from patients with multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults, predominantly females. This was partially attributed to sex differences in immunity, which are influenced by changes in sex hormones occurring during women‘s life, among other factors. Furthermore, MS patients experience significant improvement in their symptoms during pregnancy when levels of female sex-hormones significantly increase. This phenomenon was attributed to immune adaptations occurring during gestation which are regulated by paternal antigens and sex hormones. The human chorionic gonadotropin (hCG) was shown to have strong immunosuppressive abilities. We aimed to analyze here the capacity of the hCG to regulate pro- and anti-inflammatory cytokine production by PBMC from MS patients. PBMC isolated from 17 MS patients receiving IFNβ1a treatment were cultured with or without recombinant or urinary hCG. Cytokine production in the supernatants was assessed using a CBA array and cytokine production by lymphocytes and expression of co-stimulatory molecules in B-lymphocytes were evaluated by flow cytometry. hCG reduced the production of TNF by PBMC from MS patients while lowering the percentages of TNF producing T cells and diminishing the production of TNF by B cells. hCG significantly boosted the production of IL-10 by regulatory T cells and CD19high B cells from MS patients. Furthermore, hCG treatment lowered the percentages of CD80+CD86+ expressing B cells within PBMC from MS patients. Overall, our results described a novel and not yet explored mechanisms of action of hCG in the context of MS.

The impact of irritant challenge on the skin barrier and myeloid-resident immune cells in women who are postmenopausal is modulated by hormone replacement therapy.

Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear. To examine how menopause and HRT affect the skin barrier and immune cell composition in postmenopausal women following irritant challenge. Two cohorts of postmenopausal women were recruited to the study. The first cohort consisted of 10 untreated women [HRT-; mean (SEM) age 56.5 (1.6) years (range 48-63)] and the second was composed of 8 women receiving HRT [HRT+; mean (SEM) age 54.0 (2.1) years (range 48-63)]. Skin irritation was induced by applying topical sodium lauryl sulfate (SLS) 1.25% to occluded buttock skin for 48 h. Clinical assessment was conducted after 24 h, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence. Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in transepidermal water loss (P < 0.05), filaggrin deposition and cytokeratin 10 (K10)+ cell layers (P < 0.01) was observed in individuals receiving HRT compared with the HRT- group. Following SLS challenge in individuals taking HRT, a significant (P < 0.01) reduction in CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans cells (LCs). Significantly fewer migrating LCs were found in those who were not receiving HRT (P < 0.01). Furthermore, the numbers of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (P < 0.05) higher in those taking HRT following SLS challenge. Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased K10+ epidermal cell layers. Following challenge, HRT users exhibited elevated LC, inflammatory DC and macrophage counts in the dermis. These may render skin both more prone to inflammation and more capable of resolving it, while also promoting skin repair.

Cardiovascular and physiological risk factors in women at mid-life and beyond.

Cardiovascular disease (CVD) is the leading cause of death in women. After menopause, sex-specific and gender-specific factors may play an important role in increasing CVD risk, with changes in sex hormones, body fat distribution, lipid and metabolic profile, and structural and functional vascular modifications. Premature and early-onset menopause are detrimental to cardiovascular health due to the early cessation of the protective effect of endogenous estrogen. An independent association of menopause with an increased risk of CVD has been documented in early menopause (<45 years). Sex-related differences are relevant in pharmacokinetics and pharmacodynamics; different enzyme formations, drug compatibility, efficacy, and side effects vary for different sexes. Despite some progress in sex and gender research in CVD, disparities remain. Menopausal hormone therapy (MHT) is available at mid-life for symptoms of menopause and may impact cardiovascular risk. Taken early, MHT may reduce CVD morbimortality. However, this is balanced against the risk of increased thrombosis. This paper reviews physiologic changes that contribute to cardiovascular risk in postmenopausal women and discusses clinical implications. Specifically, it explores the atheroprotective effects of estrogen and MHT and the associations between menopause with lipid levels, hypertension, body composition, and diabetes for women at mid-life and beyond.

Canine and feline foetal fluids: Volume, hormonal and biochemical characterization during pregnancy.

This study aimed to evaluate the volume, the concentration of steroid hormones, and biochemical composition of the foetal fluids at different gestational ages in dogs and cats. Following the ovariohysterectomy, the allantoic and amniotic fluid samples were collected from pregnant bitches and queens and were assigned to different groups according to their gestational age. The canine and feline allantoic fluid volume increased during pregnancy, reached its maximum values on days 40-49 and then decreased. The canine and feline amniotic fluid volume increased steadily by the last days of pregnancy. In spite of significant changes of sex hormones in the foetal fluids, their concentration and ratios were not significantly different between male and female fetuses. The canine amniotic cortisol concentration increased until days 40-49 and decreased significantly afterwards. The maximum cortisol concentrations in the feline allantoic and amniotic fluids were observed on days 50-60 and 40-49, respectively. During the canine pregnancy, the concentrations of calcium, phosphorus, chloride, sodium, triglyceride, cholesterol, total protein, albumin and the activities of aminotransferase (AST), alkaline phosphatase (ALP), amylase and gamma-glutamyl transferase (GGT) in the amniotic fluid were higher than the allantoic fluid. The magnesium, potassium, lactate dehydrogenase (LDH) activity, creatine and lipase were higher in the allantoic fluid. In the feline allantoic fluid, potassium, magnesium, phosphorus, creatinine, albumin and glucose concentrations and the activities of creatine kinase (CK), GGT, LDH and lipase were higher. The ALP, AST activities, sodium and calcium concentrations were higher in the amniotic fluid (p<0.05). Volume of foetal fluids was determined in dogs and cats. Concentration of sex hormones did not different between male and female fetuses.