Non-genomic actions of steroid hormones on the contractility of non-vascular smooth muscles.

Steroid hormones play an important role in physiological processes. The classical pathway of steroid actions is mediated by nuclear receptors, which regulate genes to modify biological processes. Non-genomic pathways of steroid actions are also known, mediated by cell membrane-located seven transmembrane domain receptors. Sex steroids and glucocorticoids have several membrane receptors already identified to mediate their rapid actions. However, mineralocorticoids have no identified membrane receptors, although their rapid actions are also measurable. In non-vascular smooth muscles (bronchial, uterine, gastrointestinal, and urinary), the rapid actions of steroids are mediated through the modification of the intracellular Ca2+ level by various Ca-channels and the cAMP and IP3 system. The non-genomic action can be converted into a genomic one, suggesting that these distinct pathways may interconnect, resulting in convergence between them. Sex steroids mostly relax all the non-vascular smooth muscles, except androgens and progesterone, which contract colonic and urinary bladder smooth muscles, respectively. Corticosteroids also induce relaxation in bronchial and uterine tissues, but their actions on gastrointestinal and urinary bladder smooth muscles have not been investigated yet. Bile acids also contribute to the smooth muscle contractility. Although the therapeutic application of the rapid effects of steroid hormones and their analogues for smooth muscle contractility disorders seems remote, the actions and mechanism discovered so far are promising. Further research is needed to expand our knowledge in this field by using existing experience. One of the greatest challenges is to separate genomic and non-genomic effects, but model molecules are available to start this line of research.

Sex-Specific Acute Cerebrovascular Responses to Photothrombotic Stroke in Mice.

Mechanisms underlying cerebrovascular stroke outcomes are poorly understood, and the effects of biological sex on cerebrovascular regulation post-stroke have yet to be fully comprehended. Here, we explore the overlapping roles of gonadal sex hormones and rho-kinase (ROCK), two important modulators of cerebrovascular tone, on the acute cerebrovascular response to photothrombotic (PT) focal ischemia in mice. Male mice were gonadectomized and female mice were ovariectomized to remove gonadal hormones, whereas control ("intact") animals received a sham surgery prior to stroke induction. Intact wild-type (WT) males showed a delayed drop in cerebral blood flow (CBF) compared with intact WT females, whereby maximal CBF drop was observed 48 h following stroke. Gonadectomy in males did not alter this response. However, ovariectomy in WT females produced a "male-like" phenotype. Intact Rock2+/- males also showed the same phenotypic response, which was not altered by gonadectomy. Alternatively, intact Rock2+/- females showed a significant difference in CBF values compared with intact WT females, displaying higher CBF values immediately post-stroke and showing a maximal CBF drop 48 h post-stroke. This pattern was not altered by ovariectomy. Altogether, these data illustrate sex differences in acute CBF responses to PT stroke, which seem to involve gonadal female sex hormones and ROCK2. Overall, this study provides a framework for exploring sex differences in acute CBF responses to focal ischemic stroke in mice.

The role of sex hormones, oral contraceptive use, and its parameters on visuospatial abilities, verbal fluency, and verbal memory.

Sex hormones can cross the blood-brain barrier and access brain regions underlying higher-order cognition. Containing synthetic sex hormones, oral contraceptives (OC) have been found to modulate visuospatial and verbal abilities, though inconsistencies have been found in the literature. Among possible explanations, certain OC use parameters (progestin androgenicity, synthetic hormone levels, duration of use) have not received consistent consideration. Thus, the objectives were to (1) examine group differences between men, combined OC users, and naturally cycling women (NC women; not using OC) in visuospatial abilities, verbal fluency, and verbal memory and (2) investigate the contribution of endogenous and exogenous sex hormones on these effects. We also aimed to (3) identify OC use parameters relevant to cognitive outcomes. In total, 70 combined OC users, 53 early follicular (EF) women, 43 pre-ovulatory (PO) women, and 47 men underwent cognitive tests. Performance was compared based on hormonal milieus (OC, EF, PO, men) and OC users' contraceptive androgenicity (anti, low, high). Correlations between performance, hormone levels and OC use duration were also conducted. OC use dampened the sex difference that typically favors men in 3D visuospatial abilities, whereas its duration of use positively predicted verbal fluency. Androgenicity and hormone levels did not predict performance in any task. These results highlight the importance of considering OC use duration. Results also did not support a role for androgenicity in cognition. Importantly, combined OC use (including prolonged use) does not impair visuospatial, verbal, and memory functions in a healthy young sample.

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats.

Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (Star, Cyp11a1, Cyp17a1) and genes involved in ovulation regulation (Adamts-1, Cox-2, Egr-1, Mt-1); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.

Ecdiesteroides y su actividad farmacológica sobre el músculo esquelético / Ecdysteroids and their pharmacological activity on skeletal muscle

Introducción: Los ecdiesteroides presentan cualidades únicas dentro del reino vegetal y animal. Su similitud a esteroides endógenos de mamíferos les otorga actividad biológica sobre el tejido muscular esquelético. Sin embargo, su mecanismo de acción está por definirse en su totalidad. Método: Se realizó una revisión narrativa utilizando la evidencia científica más relevante. Se consultaron de las bases de datos Medline, Google Scholar, Scielo y Wiley, incluyéndose y excluyéndose trabajos acordes a los criterios del autor. Resultados: La actividad de los ecdiesteroides, principalmente de la Ecdisterona (Ec), podría deberse a la interacción con Mas, receptor acoplado a proteína-G transmembrana (GPCR), y la posterior activación del receptor de estrógenos β (ER β) no nuclear. Dicho mecanismo de acción induce la activación de la ruta alternativa del Sistema Renina-Angiotensina-Aldosterona (RAA) aboliendo los mecanismos de degradación muscular y, mediante la activación indirecta de Erβ, se suprime la expresión del gen de la miostatina. Esta actividad biológica pudiera conferir a los ecdiesteroides propiedades farmacológicas óptimas para impedir la degradación proteico-muscular, tales como la regeneración y reparación del tejido. Conclusiones: Ec ha demostrado poseer propiedades farmacológicas interesantes para el abordaje alternativo de patologías musculodegenerativas por sus efectos anticatabólicos. Aunque prosigue la investigación para su implementación en la clínica, esta siendo utilizada en la industria deportiva y en ensayos para el tratamiento de diferentes patologías. (AU)

Introduction: Ecdysteroids present unique qualities within the plant and animal kingdoms. Their similarity to en-dogenous mammalian steroids allows them to present biological activity on skeletal muscle tissue. However, this molecule’s action mechanism remains to be fully understood. Method: A narrative review was carried out using the most relevant scientific evidence. Different databases such as Medline, Google Scholar, Scielo and Wiley were consulted. Works were included or excluded according to the author ́s criterium. Results: Ecdysteroids’ activity, mostly that of ecdysterone, might be due to the interaction with Mas receptor, a transmembrane G-Protein Coupled Receptor (GPCR), and the subsequent indirect activation of β-Estrogen Recep-tor ́s (β-ER) non-nuclear form. Said action mechanism induces the alternative pathway activation of the Renin-An-giotensin-Aldosterone System (RAAS), abolishing muscular degradation mechanism. Finally, through β-ER activa-tion, the myostatin gene is supressed. This biological activity could provide ecdysteroids optimal pharmacological properties to prevent muscular protein degradation. These include tissue regeneration and repair. Conclusions: Due to its anticatabolic effects, Ec has shown great pharmacological properties that could make it work as an alternative treatment for degenerative muscle pathologies. Although investigations regarding Ec are still in progress, it has already been used by the sports’ industry and in several clinical trials that focus on the treatment of other diseases. (AU)

Influence of sex hormone use on sleep architecture in a transgender cohort.

STUDY OBJECTIVES: Sex differences in sleep architecture are well-documented, with females experiencing longer total sleep time, more slow wave sleep (SWS), and shorter Rapid Eye Movement (REM) sleep duration than males. Although studies imply that sex hormones could affect sleep, research on exogenous sex hormones on sleep architecture is still inconclusive. This study examined sleep architecture changes in transgender individuals after 3 months of gender-affirming hormone therapy (GAHT). METHODS: We assessed sleep architecture in 73 transgender individuals: 38 transmasculine participants who started using testosterone and 35 transfeminine participants who started using estrogens and antiandrogens. Sleep architecture was measured before GAHT and after 3 months of GAHT for 7 nights using an ambulatory single-electrode sleep EEG device. Changes in sleep architecture were analyzed using linear mixed models, and non-normally distributed outcomes were log-transformed and reported as percentages. RESULTS: In transmasculine participants, SWS decreased by 7 minutes (95% CI: -12; -3) and 1.7% (95% CI: -3%; -0.5%), REM sleep latency decreased by 39% (95% CI: -52%; -22%) and REM sleep duration increased by 17 minutes (95% CI: 7; 26) after 3 months of GAHT. In transfeminine participants, sleep architecture showed no significant changes after 3 months of GAHT. CONCLUSIONS: Sleep architecture changes after 3 months of masculinizing GAHT in line with sleep in cisgender males, while it shows no changes after feminizing GAHT. The sex-specific nature of these changes raises new questions about sex hormones and sleep. Future research should focus on studying possible underlying neural mechanisms and clinical consequences of these changes.

The Impacts of Sex Differences and Sex Hormones on Fear Extinction.

Fear extinction memories are strongly modulated by sex and hormonal status, but the exact mechanisms are still being discovered. In humans, there are some basal and task-related features in which male and female individuals differ in fear conditioning paradigms. However, analyses considering the effects of sex hormones demonstrate a role for estradiol in fear extinction memory consolidation. Translational studies are taking advantage of the convergent findings between species to understand the brain structures implicated. Nevertheless, the human brain is complex and the transfer of these findings into the clinics remains a challenge. The promising advances in the field together with the standardization of fear extinction methodologies in humans will benefit the design of new personalized therapies.

Effect of the ketogenic diet on gut microbiome composition and metabolomics in polycystic ovarian syndrome rats induced by letrozole and a high-fat diet.

OBJECTIVES: The ketogenic diet (KD) is recommended to improve polycystic ovary syndrome (PCOS); however, its mechanisms of action are unclear. We aimed to study the effects and mechanisms of action of the KD on the gut microbiome and metabolites in PCOS rats and determine whether the sex hormone regulatory effects are related to modulations of the gut microbiota and metabolites. METHODS: PCOS was induced with a high-fat diet and letrozole in the rats. A KD was fed to rats for 8 wk, serum samples were collected for biochemical analysis, and the rats' fecal samples were subjected to 16S ribosomal RNA sequencing and metabolomic analysis. RESULTS: Feeding with a KD for 8 wk suppressed body weight gain, decreased luteinizing hormone and androgen levels, and improved insulin levels. Furthermore, the KD reversed the dysregulation of the gut microbiota in PCOS rats by adjusting the ratio of firmicutes and bacteroidetes. Also, the KD was involved in hormonal metabolic pathways by reducing the levels of some metabolites (such as testosterone and 7α-hydroxytestosterone) that are closely related to gut microbes. CONCLUSIONS: The KD improved the clinical phenotype and insulin resistance in PCOS rats and altered the composition of the gut microbiome and metabolites, which were associated with androgen metabolism, representing a potential mechanism for mediating the effects of the KD on sex hormone metabolism in PCOS. However, our study found contradictory effects of KD on the gut microbiome in PCOS, which need further research.

The influence of sex steroid treatment on insular connectivity in gender dysphoria.

BACKGROUND: Sex-specific differences in brain connectivity were found in various neuroimaging studies, though little is known about sex steroid effects on insular functioning. Based on well-characterized sex differences in emotion regulation, interoception and higher-level cognition, gender-dysphoric individuals receiving gender-affirming hormone therapy represent an interesting cohort to investigate how sex hormones might influence insular connectivity and related brain functions. METHODS: To analyze the potential effect of sex steroids on insular connectivity at rest, 11 transgender women, 14 transgender men, 20 cisgender women, and 11 cisgender men were recruited. All participants underwent two magnetic resonance imaging sessions involving resting-state acquisitions separated by a median time period of 4.5 months and also completed the Bermond-Vorst alexithymia questionnaire at the initial and final examination. Between scans, transgender subjects received gender-affirming hormone therapy. RESULTS: A seed based functional connectivity analysis revealed a significant 2-way interaction effect of group-by-time between right insula, cingulum, left middle frontal gyrus and left angular gyrus. Post-hoc tests demonstrated an increase in connectivity for transgender women when compared to cisgender men. Furthermore, spectral dynamic causal modelling showed reduced effective connectivity from the posterior cingulum and left angular gyrus to the left middle frontal gyrus as well as from the right insula to the left middle frontal gyrus. Alexithymia changes were found after gender-affirming hormone therapy for transgender women in both fantasizing and identifying. CONCLUSION: These findings suggest a considerable influence of estrogen administration and androgen suppression on brain networks implicated in interoception, own-body perception and higher-level cognition.

Efficiency of Chinese medicine Bushen Huatan formula for treatment of polycystic ovary syndrome in mice via regulating gut microbiota and PPARγ pathway. / è¡¥è‚¾åŒ–ç—°æ–¹é€šè¿‡è°ƒæŽ§è‚ é“èŒåŠPPARγ通路治疗多囊卵巢综合征的机制.

OBJECTIVES: To explore the effect and mechanism of Chinese medicine Bushen Huatan formula in treatment of polycystic ovary syndrome (PCOS). METHODS: Twenty-four SPF female C57BL/6J mice were randomly divided into 3 groups with 8 animals in each group. Control group was given drinking water ad libitum; PCOS was induced by giving letrozole gavage and high-fat diet in model group and treatment group; treatment group received Bushen Huatan formula suspension for 35 d. The sex hormone levels of mice were detected by enzyme-linked immunosorbent assay. Ovary morphology was observed under light microscope after hematoxylin and eosin staining. The feces in the colon of mice were collected, and the gut microbiota was detected by 16S rRNA sequencing. The short chain fatty acids were detected by gas chromatography-mas spectrometry. The expression of peroxisome proliferator activated receptor (PPARγ) was detected by immunohistochemistry. The mRNA expression of mucin-2, occludin-1, tight junction protein zonula occludens 1 (ZO-1) and PPARγ in intestinal epithelium were detected by realtime RT-PCR. The expression of inducible nitric oxide synthase (iNOS) and PPARγ was detected by Western blotting. RESULTS: Compared with the control group, the body weight, serum levels of follicle stimulating hormone, luteinizing hormone and testosterone in the model group were increased, and serum levels of estradiol were decreased (all P<0.01); the ovarian structure under light microscope was consistent with the characteristics of PCOS. Compared with the model group, the serum levels of sex hormone and ovarian structure in treatment group were improved. The overall structure of gut microbiota in PCOS model mice changed. Compared with control group, there were significantly reduced abundance of Firmicutes, and increased abundance of Verrucomicrobia, Proteobacteria and Actinobacteria inthe model group at phylum level (all P<0.05); there were significantly reduced abundance of Lactobacillus, and increased abundance of Akkermansia, Lachnoclostridium, Lactococcus and Eubacterium_coprostanoligenes at genus level (all P<0.05). The disordered condition of gut microbiota was significantly improved in treatment group. Compared with control group, the contents of acetic acid, propionic acid and butyric acid in feces of model group were significantly decreased (all P<0.05); while the contents of propionic acid and butyric acid in treatment group were significantly increased compared with model control group (both P<0.05). Compared with control group, the mRNA expression of ZO-1 and protein expression of iNOS in model group were significantly increased, and the protein expression of PPARγ and the mRNA expressions of mucin-2 and occludin-1 were significantly decreased (all P<0.05). Compared with model group, the mRNA expression of ZO-1 and protein expression of iNOS in treatment group were decreased, and the protein expression of PPARγ and the mRNA expressions of mucin-2 and occludin-1 were increased. CONCLUSIONS: PCOS induced by letrozole high-fat diet induces microflora imbalance in mice. Chinese medicine Bushen Huatan formula may increase the level of short chain fatty acid by regulating gut microbiota, thereby activating the intestinal PPARγ pathway and improving intestinal barrier function to act as a cure for PCOS.

Sex steroid hormones and epilepsy: Effects of hormonal replacement therapy on seizure frequency of postmenopausal women with epilepsy-A systematic review.

BACKGROUND AND PURPOSE: Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri- and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE. METHODS: PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk-of-bias tool for randomized trials and ROBINS-E tool. RESULTS: Of 497 articles screened, 13 studies were included, including three human studies. One cross-sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case-control study showed an increase in comparison with controls, and a randomized clinical trial found a dose-dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results. CONCLUSIONS: There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.

Does the syrinx, a peripheral structure, constrain effects of sex steroids on behavioral sex reversal in adult canaries?

We previously confirmed that effects of testosterone (T) on singing activity and on the volume of brain song control nuclei are sexually differentiated in adult canaries: females are limited in their ability to respond to T as males do. Here we expand on these results by focusing on sex differences in the production and performance of trills, i.e., rapid repetitions of song elements. We analyzed >42,000 trills recorded over a period of 6 weeks from 3 groups of castrated males and 3 groups of photoregressed females that received Silastic™ implants filled with T, T plus estradiol or left empty as control. Effects of T on the number of trills, trill duration and percent of time spent trilling were all stronger in males than females. Irrespective of endocrine treatment, trill performance assessed by vocal deviations from the trill rate versus trill bandwidth trade-off was also higher in males than in females. Finally, inter-individual differences in syrinx mass were positively correlated with specific features of trills in males but not in females. Given that T increases syrinx mass and syrinx fiber diameter in males but not in females, these data indicate that sex differences in trilling behavior are related to sex differences in syrinx mass and syrinx muscle fiber diameter that cannot be fully suppressed by sex steroids in adulthood. Sexual differentiation of behavior thus reflects organization not only of the brain but also of peripheral structures.

Influence of sex hormones status and type of training on regional bone mineral density in exercising females.

The primary objective of this study was to examine the influence of hormonal ovarian profile and training characteristics on spine, pelvis, and total body bone mineral density (BMD) in a group of well-trained females. Forty-two eumenorrheic females, twenty-eight monophasic oral contraceptive (OC) users and thirteen postmenopausal females participated in this study. Body composition was measured by total body dual-energy X-ray absorptiometry (DXA) to determine BMD of the areas of interest. Endurance-trained premenopausal females showed lower spine BMD compared to resistance-trained premenopausal females (1.03 ± 0.1 vs. 1.09 ± 0.09 g/cm2; p = 0.025). Postmenopausal females reported lower BMD level in comparison to eumenorrheic females in pelvis (1.079 ± 0.082 vs 1.19 ± 0.115 g/cm2; p = 0.005), spine (0.969 ± 0.097 vs 1.069 ± 0.109 g/cm2; p = 0.012) and total (1.122 ± 0.08 vs 1.193 ± 0.077 g/cm2; p = 0.018) and OC users whose duration of OC use was less than 5 years (OC < 5) in pelvis (1.235 ± 0.068 g/cm2; p < 0.001) and spine (1.062 ± 0.069 g/cm2; p = 0.018). In addition, lower BMD values were found in OC users who had been using OC for more than 5 years (OC ≥ 5) than eumenorrheic females in pelvis (1.078 ± 0.086 g/cm2; p = 0.029) and spine (0.966 ± 0.08 g/cm2; p = 0.05). Likewise, OC ≥ 5 showed lower values than and OC < 5 in pelvis (p = 0.004) and spine (p = 0.047). We observed a lower spine BMD value in premenopausal endurance-trained females compared to premenopausal resistance-trained females. Moreover, this research observed that prolonged use of OCs may reduce bone mass acquisition in the spine and pelvis, even in well-trained females. Finally, postmenopausal showed lower BMD despite being exercising women.Trial registration: ClinicalTrials.gov identifier: NCT04458662.Highlights Ovarian hormonal profile should be considered when assessing BMD in female athletes.The duration of oral contraceptive use influences spine and pelvis regional BMD in exercising females.Postmenopausal women show lower BMD when compared to premenopausal females despite being exercising females.

Sexually Dimorphic Regulation of Gonadotrope Cell Hyperplasia in Medaka Pituitary via Mitosis and Transdifferentiation.

The 2 pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), regulate the reproductive function in all vertebrates. While many studies have investigated the regulation of gonadotropin production and release by sex steroid feedback, its role on the regulation of gonadotrope cell number remains unclear. Using medaka as a model and an optimized protocol to restore physiological sex steroids levels following gonadectomy, we show that gonadal sex steroids not only decrease fshb transcript levels, but also Fsh cell number in both sexes. We then investigated the origin of Fsh cell hyperplasia induced by gonadectomy. In both sexes, bromodeoxyuridine incubation shows that this is achieved via Fsh cell mitosis. In situ hybridization reveals that new Fsh cells also originate from transdifferentiating Tsh cells in females, but not in males. Both phenomena are inhibited by sex steroid supplementation via feeding. In males (but not females), gonadectomy (without recovery with sex steroid supplementation) also reduces sox2 transcript levels and Sox2-immunopositive population size, suggesting that Sox2 progenitors may be recruited to produce new Fsh cells. Opposite to Fsh cells, gonadectomy decreases lhb levels in both sexes, and levels are not restored by sex steroid supplementation. In addition, the regulation of Lh cell number also seems to be sex dependent. Removal of gonadal sex steroids stimulates Lh cell mitosis in male (like Fsh cells) but not in females. To conclude, our study provides the first evidence on sexually dimorphic mechanisms used in the fish pituitary to remodel gonadotrope populations in response to sex steroids.

Influence of hormones in multiple sclerosis: focus on the most important hormones.

Hormonal imbalance may be an important factor in the severity of multiple sclerosis (MS) disease. In this context, hormone therapy has been shown to have immunoregulatory potential in various experimental approaches. There is increasing evidence of potentially beneficial effects of thyroid, melatonin, and sex hormones in MS models. These hormones may ameliorate the neurological impairment through immunoregulatory and neuroprotective effects, as well as by reducing oxidative stress. Expanding our knowledge of hormone therapy may be an effective step toward identifying additional molecular/cellular pathways in MS disease. In this review, we discuss the role of several important hormones in MS pathogenesis in terms of their effects on immunoregulatory aspects and neuroprotection.

GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant-like effects involving BDNF actions.

Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID-19 pandemic. Accumulating evidence for neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-, cellular-, and behavioral-specific levels. The purpose of the current work was to evaluate the proliferating role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expression of the brain-derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R-GALR2 heteroreceptor complexes and analyzed morphological changes in hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes neuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R-GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant-like effects after GALR2 and the Y1R agonists intranasal administration. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R-GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of MDD or depressive-affecting diseases.

The effect of concentrated pomegranate juice on biomarkers of inflammation, oxidative stress, and sex hormones in overweight and obese women with polycystic ovary syndrome: A randomized controlled trial.

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder. Pomegranate juice (PJ) has been known to play anti-inflammatory and antioxidant roles. However, the effects of PJ on inflammation, oxidative stress, and sex hormones in PCOS patients are very little studied, and thus more studies are needed. This randomized controlled trial enrolled 44 women diagnosed with PCOS according to the Rotterdam criteria, body mass index (BMI) ≥ 25 kg/m2 , and aged 18-40 years old. Participants were randomly assigned to take 45 ml/day of concentrated PJ or a control group without intervention. Some biomarkers of sex hormones, inflammation, and oxidative stress were quantified at baseline and after the 8-week intervention. Compared with the controls, serum testosterone levels were significantly decreased in overweight and obese women with PCOS who supplemented with concentrated PJ (-0.004 ± 0.013 vs. 0.039 ± 0.013, p = .039). However, we did not observe significant differences in luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) levels and inflammation and oxidative stress factors between the two groups after adjustment for confounding variables. An 8-week supplementation with concentrated PJ could effectively improve testosterone levels in overweight and obese women with PCOS. This study was registered at www.irct.ir (IRCT20191109045383N1).

Sex Differences in Psychosis: Focus on Animal Models.

Most psychiatric illnesses, such as schizophrenia, show profound sex differences in incidence, clinical presentation, course, and outcome. Fortunately, more recently the literature on sex differences and (to a lesser extent) effects of sex steroid hormones is expanding, and in this review we have focused on such studies in psychosis, both from a clinical/epidemiological and preclinical/animal model perspective. We begin by briefly describing the clinical evidence for sex differences in schizophrenia epidemiology, symptomatology, and pathophysiology. We then detail sex differences and sex hormone effects in behavioral animal models of psychosis, specifically psychotropic drug-induced locomotor hyperactivity and disruption of prepulse inhibition. We expand on the preclinical data to include developmental and genetic models of psychosis, such as the maternal immune activation model and neuregulin transgenic animals, respectively. Finally, we suggest several recommendations for future studies, in order to facilitate a better understanding of sex differences in the development of psychosis.

Exposure to acetaminophen impairs gametogenesis and fertility in zebrafish (Danio rerio).

Acetaminophen (ACE; paracetamol) is one of the most widely used nonsteroidal anti-inflammatory drugs worldwide and is often found in aquatic systems, where it can act on nontarget species and impair fish reproduction. This study aimed to investigate the effects of chronic exposure to environmentally relevant ACE concentrations (0.5, 5 and 50 µg/L) on multiple reproductive parameters in zebrafish (Danio rerio). Gametogenesis was analyzed using histology, morphometry, cell proliferation, and apoptosis. This study also evaluated sex steroids, and prostaglandin E2 (PGE2) levels, gene expression for sex steroids and PGE2 receptors, fertilization rate, and semen quality. In females, exposure to 5 and 50 µg/L ACE induced larger and more abundant vitellogenic follicles and increased follicular atresia. In these treatments, males showed a lower proportion and proliferation of undifferentiated spermatogonia and a higher proportion of TUNEL-positive differentiated spermatogonia, spermatids, and spermatozoa, resulting in lower sperm production. ACE increased 17ß-estradiol (E2) and reduced 11-ketotestosterone levels in the testis, whereas only E2 increased in the ovaries. In both sexes, gonadal PGE2 levels were reduced. ACE at 50 µg/L induced an increase in the gene expression of androgen, estrogen, and PGE2 receptors in the ovaries, and reduced expression in the testes. Results also showed lower egg production and fertilization rate from 28 days of exposure with reduced sperm quality. These results demonstrated that ACE impairs the reproductive performance of zebrafish, affecting multiple reproductive parameters, which may be caused by the synergistic action of the imbalance of sex steroids, with a reduction of PGE2 and its receptors.

Estradiol Replacement as a Potential Enhancer of Working Memory and Neuroplasticity in Hypogonadal Trans Women.

INTRODUCTION: The cognitive effects of cross-sex hormone therapy (CSHT) are not well understood. In cisgender individuals, sex hormone therapy can impact neurotransmitter levels and structural anatomy. Similarly, in gender-diverse persons, CSHT has been associated with neural adaptations, such as growth in brain structures resembling those observed in cisgender individuals of the same sex. Hormone-related changes in learning and memory, as seen in menopause, are associated with physiological hypogonadism or a decline in hormones, such as estradiol. The present study examined the effect of estradiol administration in humans on glutamate concentration in brain regions involved in semantic and working memory (i.e., the dorsolateral prefrontal cortex [DLPFC], the posterior hippocampus, and the pregenual anterior cingulate cortex) and its relationship with memory. METHODS: Eighteen trans women (male biological sex assigned at birth) ceased CSHT for 30 days for a washout phase (t1) upon study enrollment to reach a hypogonadal state. Working and semantic memory, cognition, hormonal assays, and brain imaging were assessed. Participants resumed CSHT for 60 days for a replacement phase (t2), after which the same evaluations from t1 were repeated. RESULTS: Estradiol increased among trans women after 60 days of resumed CSHT with significant improvements in semantic memory compared to the hypogonadal phase. Working memory recall was significantly and positively correlated to glutamate in the DLPFC during the reinstatement phase, although the relationship was not moderated by levels of estradiol. DISCUSSION: These results may have clinical implications for the therapeutic effects of estradiol replacement, serving as a protective factor against cognitive decline and impairment for trans women post-gonadectomy.