A naturalistic study of plasma lipid alterations in female patients with anorexia nervosa before and after weight restoration treatment.

BACKGROUND: Plasma lipid concentrations in patients with anorexia nervosa (AN) seem to be altered. METHODS: We conducted a naturalistic study with 75 adult female patients with AN and 26 healthy female controls (HC). We measured plasma lipid profile, sex hormones and used self-report questionnaires at admission and discharge. RESULTS: Total cholesterol (median (IQR): 4.9 (1.2)) and triglycerides (TG) (1.2 (0.8)) were elevated in AN at admission (BMI 15.3 (3.4)) compared with HC (4.3 (0.7), p = 0.003 and 0.9 (0.3), p = 0.006) and remained elevated at discharge (BMI 18.9 (2.9)) after weight restoration treatment. Estradiol (0.05 (0.1)) and testosterone (0.5 (0.7)) were lower in AN compared with HC (0.3 (0.3), p = < 0.001 and 0.8 (0.5), p = 0.03) and remained low at discharge. There was no change in eating disorder symptoms. Depression symptoms decreased (33 (17) to 30.5 (19), (p = 0.007)). Regression analyses showed that illness duration was a predictor of TG, age was a predictor of total cholesterol and LDL, while educational attainment predicted LDL and TG. CONCLUSION: Lipid concentrations remained elevated following weight restoration treatment, suggesting an underlying, premorbid dysregulation in the lipid metabolism in AN that persists following weight restoration. Elevated lipid concentrations may be present prior to illness onset in AN. LEVEL OF EVIDENCE: III: Evidence obtained from well-designed cohort or case-control analytic studies.

Fat is essential for the human body. Too much fat in the blood can be a sign of underlying illness including heart disease. This study investigated how plasma lipids (fats) are affected in individuals with anorexia nervosa (AN). We included 75 adult female individuals with AN and 26 healthy female controls, and measured lipids, sex hormones, and used questionnaires upon admission and discharge from treatment. We found that low-weight individuals with AN had higher lipids than the healthy controls, and these lipids remained elevated after weight restoration treatment. Additionally, individuals with AN had lower levels of sex hormones (estradiol and testosterone) at their low weight, and they stayed low even after weight restoration treatment. Eating disorder symptoms remained unchanged, but depression symptoms decreased during treatment. In conclusion, the study suggests that individuals with AN have changes in their lipid metabolism, which persists even after weight restoration treatment. We don't know the reason behind these elevated lipids, and therefore, this should be investigated further in future study.

Health risk and germ cell toxicity of five commercially available sachet waters in Nigeria: a public health concern.

Background: Sachet water is the most common form of portable water commercially available in Nigeria. Methodology: Using the murine sperm count and sperm abnormality assay, the germ cell toxicity of five common commercially available sachet waters in Nigeria was assessed in this study. The levels of hormones such as Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and Total Testosterone (TT); and activities of catalase (CAT), alanine aminotransferase (ALT), superoxide dismutase (SOD), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were evaluated. The heavy metal and physicochemical parameters of the sachet waters were also analyzed. Healthy male mice were allowed to freely drink the sachet waters for 35 days after which they were sacrificed. Results: The findings indicated that the concentrations of some heavy metals (As, Cr, and Cd) in the sachet waters exceeded the limit by regulatory organizations. The data of the total carcinogenic risk (TCR) and total non-carcinogenic risk (THQ) of some heavy metals associated with the ingestion of sachet water for adults and children showed that the values exceeded the acceptable threshold, and thus, is indicative of a high non-carcinogenic and carcinogenic risks. The data of the sperm abnormality assay showed that in the exposed mice, the five sachet waters induced a statistically significant (P < 0.05) increase in abnormal sperm cells and a significantly lower mean sperm count. Additionally noted were changes in the serum activities of TT, FSH, ALP, AST, ALT, and LH. Conclusion: Thus, the sachet waters studied contained agents that can induce reproductive toxicity in exposed humans. This is of public health importance and calls for immediate action by regulatory bodies.

Fetal gender prediction by monitoring circulating steroid hormones and some biochemical parameters in maternal dromedary camels.

To predict the sex of the foetus, healthy pregnant dromedary camels (n = 24) were included. Blood samples were collected for measurements of progesterone, estradiol, testosterone, and cortisol as well as total proteins, albumin, glucose, creatinine, blood urea nitrogen, phosphorus, calcium, creatine kinase, alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), calcium, phosphorus, and magnesium. Statistical analysis revealed differences between pregnant camels and pregnant camels in terms of female or male foetuses depending on the actual sex of the born calf. The results revealed that testosterone and ALP concentrations were significantly (P < 0.001) greater in camels given to males than in those given to calves. There were strong positive correlations between male calf birth and testosterone and ALP concentrations (r = 0.864; P < 0.0001 and r = 0.637; P < 0.001, respectively). On the other hand, the cortisol, glucose and creatinine concentrations were significantly lower (P lower in camel calved males than in females). There were significant negative correlations between male calf birth and the cortisol, glucose and creatinine concentrations (r =-0.401; P = 0.052; r =-0.445; P = 0.029 and r =-0.400; P = 0.053, respectively). The concentrations of calcium, phosphorus, calcium/phosphorus ratio, magnesium, and albumin and the albumin/globulin ratio were not significantly different (P > 0.05) between the two groups. In conclusion, testosterone could be used as a biomarker to determine the sex of foetuses in dromedary camels.

Association of endogenous sex hormone levels with tooth loss due to periodontitis in men and post-menopausal women: The multi-ethnic study of atherosclerosis.

AIM: To investigate the association between endogenous sex hormone levels and history of tooth loss related to periodontitis in healthy middle-aged to older men and post-menopausal women. METHODS: This cross-sectional study included 5649 participants aged 45-84 (mean age, 63 ± 10 years) from the Multi-Ethnic Study of Atherosclerosis cohort who had sex hormone levels measured and answered a questionnaire regarding perceived periodontal status at exam 1. Multivariable logistic regression was used to examine the association of sex hormones (exposure) with history of tooth loss (outcome), stratified by sex. RESULTS: Among post-menopausal women, higher free testosterone (per 1SD) was associated with a greater prevalence of tooth loss [OR 1.49 (95% CI, 1.08-2.05)], whereas higher sex hormone binding globulin (SHBG) was associated with a lower prevalence of tooth loss [OR 0.74 (0.58-0.94)], after adjustment for cardiometabolic risk factors and reproductive factors. In men, higher free testosterone and lower SHBG were associated with a lower prevalent probability of tooth loss in unadjusted analysis, but these associations lost significance after covariate adjustment. CONCLUSION: A higher androgenic sex hormone profile in post-menopausal women (i.e., increased free testosterone, lower SHBG) was associated with an increased prevalence of tooth loss, after adjusting cardiometabolic risk factors. No such association was found in men. These findings suggest that sex hormones may influence or serve as a marker for periodontal health.

Emotion recognition and regulation in males: Role of sex and stress steroids.

Understanding emotions in males is crucial given their higher susceptibility to substance use, interpersonal violence, and suicide compared to females. Steroid hormones are assumed to be critical biological factors that affect and modulate emotion-related behaviors, together with psychological and social factors. This review explores whether males' abilities to recognize emotions of others and regulate their own emotions are associated with testosterone, cortisol, and their interaction. Higher levels of testosterone were associated with improved recognition and heightened sensitivity to threatening faces. In contrast, higher cortisol levels positively impacted emotion regulation ability. Indirect evidence from neuroimaging research suggested a link between higher testosterone levels and difficulties in cognitive emotion regulation. However, this notion must be investigated in future studies using different emotion regulation strategies and considering social status. The present review contributes to the understanding of how testosterone and cortisol affect psychological well-being and emotional behavior in males.

Association between Volatile Organic Compound Exposure and Sex Hormones in Adolescents: The Mediating Role of Serum Albumin.

The associations between VOCs and sex hormones in adolescents remain unclear, and the role of serum albumin in these associations deserves to be explored. We conducted cross-sectional analyses using generalized linear models (GLMs), weighted quantile sum (WQS) regression, and mediation analysis, based on data from 584 adolescents from the National Health and Nutrition Examination Survey (NHANES). The GLM analyses revealed that seven kinds of mVOCs potentially affected sex hormone levels. According to the WQS regression results, 2-aminothiazoline-4-carboxylic acid (ATCA) was the major contributor to the significant associations of mixed mVOC exposure with testosterone, estradiol, and free androgen index in males; N-acetyl-S-(N-methylcarbamoyl)-L-cysteine (AMCC) was the major contributor to the significant associations of mixed mVOC exposure with sex hormone-binding globulin in males; and N-acetyl-S-(benzyl)-L-cysteine (BMA) was the major contributor to the significant associations of mixed mVOC exposure with the ratio of testosterone to estradiol in females. Moreover, serum albumin could mediate up to 9.2% of the associations between mixed exposure to mVOCs and sex hormones. Our findings could provide a reference for studies on the mechanisms underlying the effects of VOCs on sex hormones in adolescents and emphasize the necessity of reducing exposure to ATCA, AMCC, BMA, and their parent compounds.

Simulated climate change and atrazine contamination can synergistically impair zebrafish testicular function.

Elements that interfere with reproductive processes can have profound impacts on population and the equilibrium of ecosystems. Global warming represents the major environmental challenge of the 21st century, as it will affect all forms of life in the coming decades. Another coexisting concern is the persistent pollution by pesticides, particularly the herbicide Atrazine (ATZ), which is responsible for a significant number of contamination incidents in surface waters worldwide. While it is hypothesized that climate changes will significantly enhance the toxic effects of pesticides, the actual impact of these phenomena remain largely unexplored. Here, we conducted a climate-controlled room experiment to assess the interactive effects of the projected 2100 climate scenario and environmentally realistic ATZ exposures on the reproductive function of male zebrafish. The gonadosomatic index significantly decreased in fish kept in the extreme scenario. Cellular alterations across spermatogenesis phases led to synergic decreased sperm production and increased germ cell sloughing and death. ATZ exposure alone or combined with climate change effects, disrupted the transcription levels of key genes involved in steroidogenesis, hormone signaling and spermatogenesis regulation. An additive modulation with decreased 11-KT production and increased E2 levels was also evidenced, intensifying the effects of androgen/estrogen imbalance. Moreover, climate change and ATZ independently induced oxidative stress, upregulation of proapoptotic gene and DNA damage in post-meiotic germ cell, but the negative effects of ATZ were greater at extreme scenario. Ultimately, exposure to simulated climate changes severely impaired fertilization capacity, due to a drastic reduction in sperm motility and/or viability. These findings indicate that the future climate conditions have the potential to considerably enhance the toxicity of ATZ at low concentrations, leading to significant deleterious consequences for fish reproductive function and fertility. These may provide relevant information to supporting healthcare and environmental managers in decision-making related to climate changes and herbicide regulation.

Causality between Sex Hormones and Bone Mineral Density in Childhood: Age- and Tanner-Stage-Matched Sex Hormone Level May Be an Early Indicator of Pediatric Bone Fragility.

This study aimed to investigate the impact of hypogonadism on bone mineral density (BMD) in children and adolescents with chronic diseases to determine the relationship between sex hormones and BMD. This retrospective study included 672 children and adolescents with chronic diseases such as hemato-oncologic, rheumatoid, gastrointestinal, and endocrinologic diseases. The relationship between the sex- and Tanner-stage-matched Z-scores for sex hormones and the sex- and age-matched lumbar spine BMD (LSBMD) Z-scores was evaluated. Adjustments were made for confounders such as underlying diseases, age at diagnosis, and age- and sex-matched body mass index Z-scores. Patients had a mean LSBMD Z-score of -0.55 ± 1.31. In the multivariate regression analysis, male testosterone showed a positive association with the LSBMD Z-score (p < 0.001), whereas female estradiol, luteinizing hormone, and follicular-stimulating hormone showed no significant association with the LSBMD Z-scores. In the male group, the testosterone level was associated with LSBMD Z-scores > -1.0 (p < 0.001), > -2.0 (p < 0.001), and > -3.0 (p = 0.002), while the estradiol level was associated with LSBMD Z-scores > -2.0 (p = 0.001) and > -3.0 (p = 0.002) in the female group. In conclusion, sex hormones are associated with BMD in children and adolescents with chronic diseases. Therefore, various measures may be necessary to predict future skeletal problems and improve bone health in these patients.

Effect of treatment of chronic hepatitis c virus patients with direct-acting anti-retroviral drugs on semen and hormonal parameters.

Objective: Hepatitis C virus (HCV) infection is known to influence the seminal and hormonal parameters of infected men. This study was performed to assess the effects of HCV clearance using direct-acting antiviral (DAA) agents on semen and hormonal parameters. Methods: A total of 50 patients with chronic HCV were enrolled, and conventional semen analysis was performed according to World Health Organization guidelines. Basal levels of total testosterone, free testosterone (FT), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin, and sex hormone-binding globulin (SHBG) were assessed before and 3 months after treatment with DAAs. Results: Following DAA treatment, statistically significant increases were observed in sperm motility and the proportion of grade A sperm. Additionally, the percentage of abnormal forms was significantly decreased after treatment (p=0.000). However, no significant differences were observed in semen volume, concentration, or total sperm count. Sex hormone analysis of patients after DAA treatment revealed significant increases in FT, LH, and FSH levels, along with significant decreases in SHBG, prolactin, and E2 levels. Conclusion: Following HCV clearance, we noted an improvement in sperm motility and an increase in the percentage of sperm with normal morphology. Treatment with DAAs was also associated with increased levels of FT and LH, along with decreased levels of SHBG, prolactin, and E2.

Alcohol intake and endogenous sex hormones in women: Meta-analysis of cohort studies and Mendelian randomization.

BACKGROUND: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. METHODS: Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). RESULTS: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). CONCLUSIONS: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.

PACAP-38 and sex hormones in women with migraine: exploratory analysis of a cross-sectional, matched cohort study.

BACKGROUND: Endogeneous and exogeneous sex hormones can impact the frequency and severity of migraine attacks, but the underlying mechanisms are poorly understood. In this study, we investigate the relationship between female sex hormones and Pituitary Adenylate Cyclase-Activating Polypeptide-38 (PACAP-38) concentrations in plasma of women with migraine and healthy controls, aiming to elucidate potential hormonal influences on PACAP dynamics and their relevance to migraine pathophysiology. METHODS: This analysis is part of a cross-sectional, matched-cohort study. We recruited two groups of women with episodic migraine: one with a regular menstrual cycle (M-RMC) and another undergoing combined oral contraceptive treatment (M-COC). Additionally, we included corresponding age-matched control groups without migraine for both categories (C-RMC and C-COC). For participants with a RMC, the study visits were scheduled during the perimenstrual period (menstrual cycle day 2 ± 2) and periovulatory period (day 13 ± 2). Participants using COC were examined at day 4 ± 2 of the hormone-free interval and between day 7-14 of the hormone intake phase. During these visits, PACAP-38 concentrations in plasma were measured using a commercial Enzyme-linked-immunosorbent assay (ELISA) kit. RESULTS: The study included 120 women, with 30 participants in each group. Women with migraine and a RMC had significantly higher PACAP-38 plasma concentrations compared to healthy controls at both study visits [day 2 ± 2: M-RMC: 2547.41 pg/ml (IQR 814.27 - 4473.48) vs. C-RMC: 1129.49 pg/ml (IQR 257.34 - 2684.88), p = 0.025; day 13 ± 2: M-RMC: 3098.89 pg/ml (IQR 1186.29 - 4379.47) vs. C-RMC: 1626.89 (IQR 383.83 - 3038.36), p = 0.028]. In contrast, PACAP-38 levels were comparable between migraine and control groups receiving COC. Women with migraine and a RMC exhibited higher PACAP-38 concentrations during menstruation compared to those using COC during the hormone-free interval. CONCLUSION: Systemic PACAP-38 concentrations in women vary based on the presence of migraine diagnosis and their hormonal status.

Testosterone deficiency promotes arterial stiffening independent of sex chromosome complement.

BACKGROUND: Sex hormones and sex chromosomes play a vital role in cardiovascular disease. Testosterone plays a crucial role in men's health. Lower testosterone level is associated with cardiovascular and cardiometabolic diseases, including inflammation, atherosclerosis, and type 2 diabetes. Testosterone replacement is beneficial or neutral to men's cardiovascular health. Testosterone deficiency is associated with cardiovascular events. Testosterone supplementation to hypogonadal men improves libido, increases muscle strength, and enhances mood. We hypothesized that sex chromosomes (XX and XY) interaction with testosterone plays a role in arterial stiffening. METHODS: We used four core genotype male mice to understand the inherent contribution of sex hormones and sex chromosome complement in arterial stiffening. Age-matched mice were either gonadal intact or castrated at eight weeks plus an additional eight weeks to clear endogenous sex hormones. This was followed by assessing blood pressure, pulse wave velocity, echocardiography, and ex vivo passive vascular mechanics. RESULTS: Arterial stiffening but not blood pressure was more significant in castrated than testes-intact mice independent of sex chromosome complement. Castrated mice showed a leftward shift in stress-strain curves and carotid wall thinning. Sex chromosome complement (XX) in the absence of testosterone increased collagen deposition in the aorta and Kdm6a gene expression. CONCLUSION: Testosterone deprivation increases arterial stiffening and vascular wall remodeling. Castration increases Col1α1 in male mice with XX sex chromosome complement. Our study shows decreased aortic contractile genes in castrated mice with XX than XY sex chromosomes.

Cardiovascular disease is the leading cause of death worldwide. Cardiovascular disease presents differently in men and women. While men develop plaque buildup in large arteries, women develop buildup in the microvessels in the heart. Arterial stiffening, which is the hardening of arteries, increases with age in both men and women. Aging, coupled with the decline in sex hormones, exacerbates cardiovascular disease in women compared to men. Men with XY sex chromosomes have higher circulating testosterone, while women with XX sex chromosomes have increased circulating estradiol. The potential benefits of sex hormone replacement therapy are shown in men and women. Indeed, testosterone replacement deficiency is associated with adverse cardiovascular outcomes in men. Whether adverse events are dependent or independent of sex hormones' interaction with sex chromosomes is unknown. This study used the four core genotype mice comprising males with either XX or XY sex chromosome complement. We show castration increases arterial stiffening and collagen deposition on the arterial wall. We also identified the escapee and smooth muscle contractile genes that may play a role in arterial stiffening. Our data suggests that testosterone deprivation mediates arterial stiffening and remodeling.

Effect of Sleeve Gastric Surgery on Body Weight and Hypothalamic-Pituitary Axis Hormone Levels in Patients with Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disorder in women of reproductive age. It is difficult for patients with PCOS to achieve weight loss with conventional treatment. The aim of this study was to investigate weight loss and changes in hypothalamic-pituitary axis hormone levels in patients with PCOS combined with obesity after sleeve gastrectomy. METHODS: A retrospective analysis of 12 patients without PCOS and 24 patients with PCOS who underwent bariatric surgery at Beijing Luhe hospital from 2020 to 2022 was performed. The study assessed the changes in body weight and hormonal indexes of the hypothalamic-pituitary axis before and six months after the surgery. RESULTS: Patients with PCOS experienced greater weight loss compared to those without the condition. Following surgery, individuals with PCOS showed lower levels of postoperative testosterone, prolactin, and free testosterone indices compared to preoperative levels. Additionally, postoperative LH and FSH levels were higher than preoperative levels. Analysis of thyroid axis hormone levels revealed that FT3 and TSH levels were notably reduced in patients with PCOS postoperatively. Furthermore, growth hormone levels were found to be elevated in patients with PCOS following surgery. CONCLUSION: Bariatric surgery enhances hormone levels in the hypothalamic-pituitary axis in women with PCOS, leading to greater improvements in patients with PCOS compared to those with simple obesity.

Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and fatality rate in men than women. However, the mechanism by which androgen mediates aortic aneurysms is largely unknown. Herein, we found that male mice, not female mice, developed aortic aneurysms when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (AR) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and aortic aneurysms. We demonstrated that administration of anti-PD-1 Ab and adoptive PD-1 deficient T cell transfer reinstated Aldo-salt-induced aortic aneurysms in orchiectomized mice, and genetic deletion of PD-1 exacerbated aortic aneurysms induced by high-fat diet and angiotensin II (Ang II) in non-orchiectomized mice. Mechanistically, we discovered that AR bound to the PD-1 promoter to suppress its expression in the spleen. Thus, our study unveils a mechanism by which androgen aggravates aortic aneurysms by suppressing PD-1 expression in T cells. Moreover, our study suggests that some cancer patients might benefit from screenings for aortic aneurysms during immune checkpoint therapy.

Proto-Endocrinological Theories of Masculinity/Femininity (1490-1904).

From the mid-seventeenth century, resorption of a testicular "ferment" and resorption of some part of the semen constituted reputable accounts of secondary sexual characteristics. Only in the early twentieth century was the latter, "recrementitious secretion" theory, explicitly considered superseded by one of internal secretion, an advance ushering in the hormone era. A reconstruction of these proto-endocrinological concepts is offered onward from the first, 1490 print edition of Galen's On Semen. Early modern physicians picking up from Galen deliberated widely on the medium and pathway of male and female testicular influences on "the entire body," including the mind, causing "femininity" and "masculinity" in physical, mental-temperamental, and behavioral terms. A switch is discernible from "heat and strength" (Galen) to blood-borne "virility" or testicular vapor (such as proposed in 1564 by Tomás Rodrigues da Veiga), to iatrochemical postulations of a "seminal ferment" (suggested in the late 1650s, perhaps independently, by Thomas Willis at Oxford and Lambert van Velthuysen in Utrecht), finally to a "seminal recrement" or "reabsorbed semen" concept soon after (emergent in the posthumous work of Giovanni Alfonso Borelli, among others). During the late eighteenth century, mounting controversy surrounded both the very idea of that concept and the involved anatomical pathways, informed by multiple experiments.

Implications of innate immune sexual dimorphism for MASLD pathogenesis and treatment.

Growing evidence suggests that metabolic dysfunction-associated steatotic liver disease (MASLD) is significantly higher in men versus women. Increased prevalence is observed in postmenopausal women, suggesting that age and sex (hormones) influence MASLD development and progression. Molecular data further reveal that sex regulates the innate immune responses with an essential role in MASLD progression. To date, there has been limited focus on the role of innate immune sexual dimorphism in MASLD, and differences between men and women are not considered in the current drug discovery landscape. In this review, we summarize the sex disparities and innate immune sexual dimorphism in MASLD pathogenesis. We further highlight the importance of harnessing sexual dimorphism in identifying therapeutic targets, developing pharmacological therapies, and designing (pre-) clinical studies for the personalized treatment for MASLD.

Paediatric gender medicine: Longitudinal studies have not consistently shown improvement in depression or suicidality.

AIM: Systematic literature reviews have found the evidence for hormonal interventions in paediatric-age patients with gender dysphoria is of low certainty. Studies in this field have all been observational, and generally of low quality. Nevertheless, some experts assert that the observational studies in this field have consistently found improvement in mental health, and therefore constitute sufficient evidentiary basis for hormonal interventions. The present review sought to characterise results of the longitudinal clinical research studies that have reported depression and suicidality outcomes. METHODS: The present review collated, from examination of six existing reviews, 14 longitudinal clinical research studies that have specifically investigated depression and/or suicidality outcomes. RESULTS: Significantly positive depression outcomes were reported in six studies, and significantly positive suicidality outcomes in two studies. Outcomes were negative in the largest study. Notably, some studies articulated positive conclusions about hormonal interventions even in the setting of insignificant, small or negative findings. CONCLUSIONS: Analysis of longitudinal clinical research in this field showed inconsistent demonstration of benefit with respect to depression and suicidality. This analysis suggests that, contrary to assertions of some experts and North American professional medical organisations, the impact of hormonal interventions on depression and suicidality in this population is unknown.

Chronic administration of cannabinoid agonists ACEA (CB1), AM1241 (CB2), and CP55,940 (mixed CB1/CB2) 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 anti-allodynic efficacy of CB1-selective (ACEA), CB2-selective (AM1241), and CB1/CB2 mixed (CP55,940) 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 anti-allodynic effects, with females developing tolerance more rapidly than males, while the anti-allodynic 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 CB¬2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB¬2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB¬2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

The elucidation of species-specific receptor pharmacology: a case study using subtype selective para- and meta-carborane estrogen receptor agonists.

Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) ß is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERß without activating α is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERß-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine estrogen receptors. In vivo selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the in vivo pharmacokinetics of the analogs following single dose IV and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERß-12 for human ERß. However, like others in the meta-carborane series, its poor in vivo pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and in vitro human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK293 cells expressing murine estrogen receptors revealed species-specific differences in the ER-subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. Significance Statement This study investigates para- and meta-substituted carborane analogs targeting estrogen receptors, revealing the greater selectivity of carborane analogs for human ERß compared to the mouse homolog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.

Association between systemic immunity-inflammation index and sex hormones in children and adolescents aged 6-19.

Objectives: This study aimed to evaluate the relationship between systemic immune-inflammation index (SII) and sex hormones in children and adolescents aged 6-19 years. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. Inclusion criteria comprised subjects aged 6-19 years with complete data on both SII and sex hormones. We employed weighted multiple regression analysis and subgroup analytical methods to independently estimate the relationship between SII and sex hormones. Results: In this study, a total of 3767 participants were included, with an average age of 12.32 ± 3.95 years. Males constituted 50.54%, and females 49.46%. Among males, a statistically significant negative correlation emerged between SII and sex hormone-binding globulin (SHBG). Similarly, in the female population, SII exhibited a statistically significant negative correlation with total testosterone (TT), SHBG, and the Ratio of TT to estradiol, while maintaining a positive correlation with free androgen index (FAI). Subgroup analysis underscored variances in the association between sex hormones and SII within cohorts distinguished by pubertal status or different body mass index (BMI). In addition, the relationship between SII and estradiol exhibited nonlinearity. Employing a two-segment linear regression model, we identified an inverted U-shaped association between SII and estradiol, with an inflection point of 748.09 (1000cell/ml). Conclusion: Our findings suggest that SII may be an independent risk factor for changes in sex hormones in both male and female children and adolescents. More prospective and experimental studies should be conducted to validate our results and elucidate the underlying molecular pathways.