Reproductive function and behaviors: an update on the role of neural estrogen receptors alpha and beta.

Infertility is becoming a major public health problem, with increasing frequency due to medical, environmental and societal causes. The increasingly late age of childbearing, growing exposure to endocrine disruptors and other reprotoxic products, and increasing number of medical reproductive dysfunctions (endometriosis, polycystic ovary syndrome, etc.) are among the most common causes. Fertility relies on fine-tuned control of both neuroendocrine function and reproductive behaviors, those are critically regulated by sex steroid hormones. Testosterone and estradiol exert organizational and activational effects throughout life to establish and activate the neural circuits underlying reproductive function. This regulation is mediated through estrogen receptors (ERs) and androgen receptor (AR). Estradiol acts mainly via nuclear estrogen receptors ERα and ERß. The aim of this review is to summarize the genetic studies that have been undertaken to comprehend the specific contribution of ERα and ERß in the neural circuits underlying the regulation of the hypothalamic-pituitary-gonadal axis and the expression of reproductive behaviors, including sexual and parental behavior. Particular emphasis will be placed on the neural role of these receptors and the underlying sex differences.

Egg-laying hormone expression in identified neurons across developmental stages and reproductive states of the nudibranch Berghia stephanieae.

Neuropeptides play essential roles in coordinating reproduction. Egg-laying hormone (ELH) is conserved in genetic sequence and behavioral function across molluscs, where neuronal clusters secrete ELH to modulate and induce egg-laying. Here we investigated ELH in the nudibranch mollusc, Berghia stephanieae. ELH preprohormone gene orthologs, which showed clade-specific differences at the C-terminus of the predicted bioactive peptide, were identified in brain transcriptomes across several nudipleuran species, including B. stephanieae. ELH shares deep homology with the corticotropin-releasing hormone gene family, which has roles broadly in stress response. Injection of synthesized B. stephanieae ELH peptide into mature individuals induced egg-laying. ELH gene expression in the brain and body was mapped using in-situ hybridization chain reaction. Across the adult brain, 300-400 neurons expressed ELH. Twenty-one different cell types were identified in adults, three of which were located unilaterally on the right side, which corresponds to the location of the reproductive organs. Ten cell types were present in pre-reproductive juvenile stages. An asymmetric cluster of approximately 100 small neurons appeared in the right pedal ganglion of late-stage juveniles. Additional neurons in the pleural and pedal ganglia expressed ELH only in adults that were actively laying eggs and sub-adults that were on the verge of doing so, implicating their direct role in reproduction. Outside the brain, ELH was expressed on sensory appendages, including in presumptive sensory neurons. Its widespread expression in the nudibranch B. stephanieae suggests that ELH plays a role beyond reproduction in gastropod molluscs.

Molecular and functional mapping of the neuroendocrine hypothalamus: a new era begins.

BACKGROUND: Recent advances in neuroscience tools for single-cell molecular profiling of brain neurons have revealed an enormous spectrum of neuronal subpopulations within the neuroendocrine hypothalamus, highlighting the remarkable molecular and cellular heterogeneity of this brain area. RATIONALE: Neuronal diversity in the hypothalamus reflects the high functional plasticity of this brain area, where multiple neuronal populations flexibly integrate a variety of physiological outputs, including energy balance, stress and fertility, through crosstalk mechanisms with peripheral hormones. Intrinsic functional heterogeneity is also observed within classically 'defined' subpopulations of neuroendocrine neurons, including subtypes with distinct neurochemical signatures, spatial organisation and responsiveness to hormonal cues. AIM: The aim of this review is to critically evaluate past and current research on the functional diversity of hypothalamic neuroendocrine neurons and their plasticity. It focuses on how this neuronal plasticity in this brain area relates to metabolic control, feeding regulation and interactions with stress and fertility-related neural circuits. CONCLUSION: Our analysis provides an original framework for improving our understanding of the hypothalamic regulation of hormone function and the development of neuroendocrine diseases.

The Pattern of GH Action in the Mouse Brain.

GH acts in numerous organs expressing the GH receptor (GHR), including the brain. However, the mechanisms behind the brain's permeability to GH and how this hormone accesses different brain regions remain unclear. It is well-known that an acute GH administration induces phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in the mouse brain. Thus, the pattern of pSTAT5 immunoreactive cells was analyzed at different time points after IP or intracerebroventricular GH injections. After a systemic GH injection, the first cells expressing pSTAT5 were those near circumventricular organs, such as arcuate nucleus neurons adjacent to the median eminence. Both systemic and central GH injections induced a medial-to-lateral pattern of pSTAT5 immunoreactivity over time because GH-responsive cells were initially observed in periventricular areas and were progressively detected in lateral brain structures. Very few choroid plexus cells exhibited GH-induced pSTAT5. Additionally, Ghr mRNA was poorly expressed in the mouse choroid plexus. In contrast, some tanycytes lining the floor of the third ventricle expressed Ghr mRNA and exhibited GH-induced pSTAT5. The transport of radiolabeled GH into the hypothalamus did not differ between wild-type and dwarf Ghr knockout mice, indicating that GH transport into the mouse brain is GHR independent. Also, single-photon emission computed tomography confirmed that radiolabeled GH rapidly reaches the ventral part of the tuberal hypothalamus. In conclusion, our study provides novel and valuable information about the pattern and mechanisms behind GH transport into the mouse brain.

The Effect of Preoperative Cabergoline on Prolactinoma Fibrosis: A Case Series.

Introduction Prolactinomas are a common intracranial neoplasm and constitute most pituitary tumors. Although patients can present with variable hormone dysregulation and symptom severity, the use of dopamine agonists remains a first-line treatment. While bromocriptine has been found to increase tumor fibrosis, the effect of cabergoline on collagen deposition has been disputed. The aim of this article is to understand the influence of cabergoline on tumor fibrosis prior to resection. Case Presentations Four male patients who underwent prolactinoma resection were included in this report. The average age was 39.8 years (range: 26-52 years). Pre-treatment prolactin levels ranged from 957.8 to 16,487.4 ng/mL. Three patients received cabergoline for at least 1 month prior to surgery (treatment range: 1-6 months). One patient had surgery without prior cabergoline use. Pathology reports confirmed each tumor to be of lactotroph origin. For each sample, Masson's trichrome staining was performed and the percentage of sample fibrosis was quantified using an artificial intelligence imaging software. Among those who received preoperative cabergoline, the extent of tumor fibrosis was in the range of 50 to 70%. In contrast, specimen fibrosis was approximately 15% without cabergoline use. Conclusion This report demonstrates that a short duration of preoperative cabergoline can cause significant prolactinoma fibrosis. Understanding the effect of cabergoline on tumor consistency prior to surgery is essential as increased fibrosis can lead to more difficult tumor removal, reduce the extent of resection, and increase surgical complications. Considering these effects, further studies regarding the use of surgery prior to cabergoline for prolactinoma management are warranted.

Panhypopituitarism in a Patient with Burkitt Lymphoma: A Diagnostic and Therapeutic Challenge.

Pituitary infiltration by systemic lymphoma is an exceedingly rare occurrence. Given its high mortality rate, it is crucial to recognize its clinical, biochemical and radiological features in order to provide timely intervention. We present the case of a 26-year-old male with a history of human immunodeficiency virus (HIV) infection who presented to the hospital with severe anemia, persistent fever, weight loss and diarrhea over the previous 4 months. Physical examination revealed a compromised general condition, fever, pallor, hepatomegaly and lymphadenopathy. Cervical lymph node biopsy confirmed Burkitt lymphoma (BL). During hospitalization, the patient developed polyuria, polydipsia, hypernatremia, fluid-resistant hypotension and hypoglycaemia. Corticosteroid therapy was initiated due to suspected adrenal insufficiency, resulting in clinical improvement but exacerbation of polyuria and hypernatremia. Plasma and urinary osmolarity confirmed arginine vasopressin deficiency, and assessment of anterior pituitary reserve revealed hypopituitarism, necessitating hormonal replacement therapy. Sellar magnetic resonance imaging with contrast revealed pituitary infiltration. The patient subsequently developed septic shock and died. BL accounts for approximately 10% of the cases of pituitary infiltration associated with lymphoma. Clinical presentation is heterogeneous, with panhypopituitarism often serving as the initial manifestation. Sellar magnetic resonance imaging plays a pivotal role in the differential diagnosis. Management typically entails chemotherapy, immunotherapy, radiation and hormonal replacement therapy. This case report describes a patient with BL and HIV infection who developed panhypopituitarism due to pituitary infiltration, an exceedingly rare presentation considered a medical emergency.

Co-exposure to Aluminium and Cadmium Mediates Postpartum Maternal Variation in Brain Architecture and Behaviour of Mice; Involvement of Oxido-nitrergic and Cholinergic Mechanisms : Postpartum effects of Aluminium and Cadmium co-exposure in pregnancy.

Most research has not been done on the possible relationship between pregnant women's cross-metal exposures and postpartum neuroendocrine functions. The purpose of this study was to look into how co-exposure to aluminium chloride (AlCl3) and cadmium chloride (CdCl2) affected the neuroendocrine and neurometabolic changes in postpartum mice. A total of 24 adult pregnant female mice were used for the study. Group 1 served as control and received neither AlCl3 nor CdCl2 (n=6), group 2 comprised pregnant mice treated with AlCl3 (10mg/kg), group 3 with CdCl2 (1.5mg/kg), group 4 with a combination of AlCl3 (10 mg/kg) and CdCl2 (1.5 mg/kg).Oral treatment of animals was done daily from gestation day 7 to gestation day 20. Upon delivery and weaning on postnatal day 21 (PND 21), behavioural assessment was done on the postpartum mice and immediately followed by sacrifice for assessment of histological and neuroendocrine markers. Our findings revealed that the brain-to-body weight ratio was affected and brain oxidative stress was elevated in mice exposed to AlCl3 and CdCl2 during pregnancy. Given the strong association between postpartum hyperactivity, social interaction index, brain catalase and acetylcholinesterase activity, and the brain/body weight ratio, it is plausible that these effects have played a role in the adverse behavioural abnormalities observed in the postpartum maternal mice. Moreover, it was noted that in certain situations, co-exposures to the metals tended to have opposite effects to single metal exposures.

Phoenixin knockout mice show no impairment in fertility or differences in metabolic response to a high-fat diet, but exhibit behavioral differences in an open field test.

Phoenixin (PNX) is a conserved secreted peptide that was identified 10 years ago with numerous studies published on its pleiotropic functions. PNX is associated with estrous cycle length, protection from a high-fat diet, and reduction of anxiety behavior. However, no study had yet evaluated the impact of deleting PNX in the whole animal. We sought to evaluate a mouse model lacking the PNX parent gene, small integral membrane protein 20 (Smim20), and the resulting effect on reproduction, energy homeostasis, and anxiety. We found that the Smim20 knockout mice had normal fertility and estrous cycle lengths. Consistent with normal fertility, the hypothalamii of the knockout mice showed no changes in the levels of reproduction-related genes, but the male mice had some changes in energy homeostasis-related genes, such as melanocortin receptor 4 (Mc4r). When placed on a high-fat diet, the wildtype and knockout mice responded similarly, but the male heterozygous mice gained slightly less weight. When placed in an open field test box, the female knockout mice traveled less distance in the outer zone, indicating alterations in anxiety or locomotor behavior. In summary, the homozygous knockout of PNX did not alter fertility and modestly alters a few neuroendocrine genes in response to a high-fat diet, especially in the female mice. However, it altered the behavior of mice in an open field test. PNX therefore may not be crucial for reproductive function or weight, however, we cannot rule out possible compensatory mechanisms in the knockout model. Understanding the role of PNX in physiology may ultimately lead to an enhanced understanding of neuroendocrine mechanisms involving this enigmatic peptide.

Hypothalamic GABAergic Neurons Expressing Cellular Retinoic Acid Binding Protein 1 (CRABP1) Are Sensitive to Metabolic Status and Liraglutide in Male Mice.

INTRODUCTION: Owing to their privileged anatomical location, neurons of the arcuate nucleus of the hypothalamus (ARC) play critical roles in sensing and responding to metabolic signals such as leptin and glucagon-like peptide 1 (GLP-1). In addition to the well-known proopiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons, subpopulations of GABAergic neurons are emerging as key regulators of energy balance. However, the precise identity of these metabolic neurons is still elusive. Here, we identified and characterized the molecular signature of a novel population of GABAergic neurons of the ARC expressing Cellular retinoic acid binding protein 1 (Crabp1). METHODS: Using a combination of immunohistochemistry and in situ hybridization techniques, we investigated the expression of Crabp1 across the mouse brain and characterized the molecular identity of Crabp1ARC neurons. We also determined whether Crabp1ARC neurons are sensitive to fasting, leptin, and GLP1R agonism by assessing cFOS immunoreactivity as a marker of neuronal activity. RESULTS: Crabp1ARC neurons represent a novel GABAergic neuronal population robustly enriched in the ARC and are distinct from the prototypical melanocortin neurons. Crabp1ARC neurons overlap with three subpopulations of yet uncharacterized ARC neurons expressing Htr3b, Tbx19, and Tmem215. Notably, Crabp1ARC neurons express receptors for metabolic hormones and their activity is modulated by the nutritional state and GLP1R agonism. CONCLUSION: Crabp1ARC neurons represent a novel heterogeneous population of GABAergic neurons sensitive to metabolic status.

Polycystic ovary syndrome (PCOS): progress towards a better understanding and treatment of the syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. It has a strong hereditary component estimated at 60 to 70% in daughters. It has been suggested that environmental factors during the fetal period may be involved in the development of the syndrome in adulthood. However, the underlying mechanisms of its transmission remain unknown, thus limiting the development of effective therapeutic strategies.This article highlights how an altered fetal environment (prenatal exposure to high levels of anti-Müllerian hormone) can contribute to the onset of PCOS in adulthood and lead to the transgenerational transmission of neuroendocrine and metabolic traits through alterations in the DNA methylation process.The originality of the translational findings summarized here involves the identification of potential biomarkers for early diagnosis of the syndrome, in addition to the validation of a promising therapeutic avenue in a preclinical model of PCOS, which can improve the management of patients suffering from the syndrome.

Le syndrome des ovaires polykystiques (SOPK) est le trouble endocrinien et métabolique le plus répandu chez les femmes en âge de procréer, avec une forte composante héréditaire estimée entre 60 et 70%. Les facteurs environnementaux pendant la période fœtale pourraient être impliqués dans l'apparition du syndrome à l'âge adulte. Néanmoins, les mécanismes sous-jacents à sa transmission demeurent inconnus, limitant ainsi le développement de thérapies efficaces.Cet article met en lumière comment un environnement fœtal altéré (exposition prénatale à des taux élevés d'hormone anti-müllerienne) pourrait contribuer à la survenue du SOPK chez la descendance ainsi qu'à la transmission transgénérationnelle des caractéristiques neuroendocriniennes et métaboliques du SOPK, par le biais d'une altération du processus de la méthylation de l'ADN.L'originalité des travaux translationnels présentés ici repose d'une part sur l'identification de potentiels biomarqueurs de diagnostic précoce du syndrome. Et d'autre part, sur la validation d'une piste thérapeutique prometteuse dans un modèle préclinique de SOPK, offrant ainsi des perspectives d'amélioration de la prise en charge des patientes atteintes de ce syndrome.

Neuroendocrinology of Reproduction and Social Behaviors in Reptiles: Advances Made in the Last Decade.

Among amniotes, reptiles are ectothermic and are clearly distinguished from mammals and birds. Reptiles show great diversity not only in species numbers, but also in ecological and physiological features. Although their physiological diversity is an interesting research topic, less effort has been made compared to that for mammals and birds, in part due to lack of established experimental models and techniques. However, progress, especially in the field of neuroendocrinology, has been steadily made. With this process, basic data on selected reptilian species have been collected. This review article presents the progress made in the last decade, which includes 1) behavioral regulation by sex steroid hormones, 2) regulation of seasonal reproduction by melatonin and GnRH, and 3) regulation of social interaction by arginine vasotocin. Through these research topics, we provide insights into the physiology of reptiles and the latest findings in the field of amniote neuroendocrinology.

DHEA and response to antidepressant treatment: A Mendelian Randomization analysis.

Treatment response is hard to predict and detailed mechanisms unknown. Lower levels of the dehydroepiandrosterone sulphate (DHEA(S)) - a precursor to testosterone and estrogen - have been associated to depression and to response to antidepressant treatment. Previous studies however may have been ridden by confounding and reverse causation. The aim of this study is to evaluate whether higher levels of DHEA(S) are causally linked to response to antidepressants using mendelian randomization (MR). We performed a Two-sample MR analysis using data the largest publicly available GWAS of DHEA(S) levels (n = 14,846) using eight common genetic variants associated to DHEA(S) (seven single nucleotide polymorphisms and one variant rs2497306) and the largest GWAS of antidepressant response (n = 5218) using various MR methods (IVW, MR Egger, Weighted mean, weighted mode, MR-PRESSO) and single SNP analysis. We further investigated for pleiotropy conducting a look up on PhenoScanner and GWAS Catalog. Results show no evidence for DHEA(S) gene risk score from any of MR methods, however, we found a significant association on individual variant analysis for rs11761538, rs17277546, and rs2497306. There was some evidence for heterogeneity and pleiotropy. This is the first paper to show some evidence for a causal association of genetically-predicted DHEA and improvement of depressive symptoms. The effect is not a simple linear effect, and we were unable to dissect whether the effect was direct effect of DHEA(S), mediated by DHEA(S) or on the pathway is not yet clear. Further studies using more refined instrumental variables will help clarify this association.

Vitamin D and behavioral disorders in older adults: results from the CLIP study.

OBJECTIVES: Vitamin D is involved in brain health and function. Our objective was to determine whether vitamin D deficiency was associated with behavioral disorders in geriatric patients. DESIGN: The observational cross-sectional CLIP (Cognition and LIPophilic vitamins) study. The report followed the STROBE statement. SETTING: Geriatric acute care unit in a tertiary university hospital in France for 3 months at the end of winter and beginning of spring. PARTICIPANTS: 272 patients ≥65 years consecutively hospitalized or seen in consultation. MEASUREMENTS: Participants were separated into two groups according to vitamin D deficiency (i.e., serum 25-hydroxyvitamin D ≤25 nmol/L). Behavior was assessed using the reduced version of the Neuropsychiatric Inventory Scale (NPI-R) score and subscores. Age, sex, BMI, education level, comorbidities, MMSE and GDS scores, use psychoactive drugs and vitamin D supplements, and serum concentrations of calcium, parathyroid hormone, TSH and estimated glomerular filtration rate (eGFR) were used as potential confounders. RESULTS: Participants with vitamin D deficiency (n = 78) had similar NPI-R score (17.4 ± 20.3 versus 17.2 ± 16.1, p = 0.92) but higher (i.e., worse) subscore of agitation and aggressiveness (2.0 ± 3.3 versus 1.2 ± 2.4, p = 0.02) and higher (i.e., worse) subscore of disinhibition (0.99 ± 2.98 versus 0.38 ± 1.42, p = 0.02) than those without vitamin D deficiency (n = 194). In multiple linear regressions, vitamin D deficiency was inversely associated with the subscore of agitation and aggressiveness (ß = 1.37, p = 0.005) and with the subscore of disinhibition (ß = 0.96, p = 0.008). CONCLUSION: Vitamin D deficiency was associated with more severe subscores of agitation and aggressiveness and of disinhibition among older adults. This provides a scientific basis to test the efficacy of vitamin D supplementation on behavioral disorders in older patients with vitamin D deficiency.

Exploring clinical applications and long-term effectiveness of benzodiazepines: An integrated perspective on mechanisms, imaging, and personalized medicine.

Benzodiazepines have been long-established treatments for various conditions, including anxiety disorders and insomnia. Recent FDA warnings emphasize the risks of misuse and dependence associated with benzodiazepines. This article highlights their benefits and potential drawbacks from various perspectives. It achieves this by explaining how benzodiazepines work in terms of neuroendocrinology, immunomodulation, sleep, anxiety, cognition, and addiction, ultimately improving their clinical effectiveness. Benzodiazepines play a regulatory role in the HPA axis and impact various systems, including neuropeptide Y and cholecystokinin. Benzodiazepines can facilitate sleep-dependent memory consolidation by promoting spindle wave activity, but they can also lead to memory deficits in older individuals due to reduced slow-wave sleep. The cognitive effects of chronic benzodiazepines use remain uncertain; however, no adverse findings have been reported in clinical imaging studies. This article aims to comprehensively review the evidence on benzodiazepines therapy, emphasizing the need for more clinical studies, especially regarding long-term benzodiazepines use.

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

IMPORTANCE: A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. OBJECTIVE: We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. SETTINGS: We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. RESULTS: One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. CONCLUSIONS AND RELEVANCE: Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

Gastrointestinal hormones: History, biology, and measurement.

This chapter attempts to provide an all-round picture of a dynamic and major branch of modern endocrinology, i.e. the gastrointestinal endocrinology. The advances during the last half century in our understanding of the dimensions and diversity of gut hormone biology - inside as well as outside the digestive tract - are astounding. Among major milestones are the dual brain-gut relationship, i.e. the comprehensive expression of gastrointestinal hormones as potent transmitters in central and peripheral neurons; the hormonal signaling from the enteroendocrine cells to the brain and other extraintestinal targets; the role of gut hormones as growth and fertility factors; and the new era of gut hormone-derived drugs. Accordingly, gastrointestinal hormones have pathogenetic roles in major metabolic disorders (diabetes mellitus and obesity); in tumor development (common cancers, sarcomas, and neuroendocrine tumors); and in cerebral diseases (anxiety, panic attacks, and probably eating disorders). Such clinical aspects require accurate pathogenetic and diagnostic measurements of gastrointestinal hormones - an obvious responsibility for clinical chemistry/biochemistry. In order to obtain a necessary insight into today's gastrointestinal endocrinology, the chapter will first describe the advances in gastrointestinal endocrinology in a historical context. The history provides a background for the subsequent description of the present biology of gastrointestinal hormones, and its biomedical consequences - not least for clinical chemistry/biochemistry with its specific responsibility for selection of appropriate assays and reliable measurements.

In silico insights into intra- and inter-species interactions of piscine gonadotropin hormones and receptor crosstalk.

In mammals, the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are macromolecules secreted during specific reproductive phases and display strict specificity towards their cognate receptors. However, fish gonadotropins (GTH) and their receptors (GTHR) display diverse species-specific expression patterns, secretion patterns, and intra- and interspecies cross-activation. To uncover the molecular basis of this diversity, we generated and analyzed 29 in-silico models of intra- and inter-species combinations of sturgeon, carp, tilapia, and human gonadotropins with piscine receptors and analyzed the resulting receptor activation and signal transduction of these GTHR-GTH complexes in-vitro. Our results suggest that unlike humans, the surface charge on piscine FSH/LH ß-seatbelt and N107huLHCGR/K104hFSHR homologs does not necessarily determine binding specificity. Instead, sequence and structural variations allow piscine GTHs significant conformational flexibility when binding to the receptor extracellular domain, thereby enabling cross-activation. The resulting diversity may support various reproductive strategies in different environmental niches.

Androgen receptor deficiency is associated with reduced aromatase expression in the ventromedial hypothalamus of male cichlids.

Social behaviors are regulated by sex steroid hormones, such as androgens and estrogens. However, the specific molecular and neural processes modulated by steroid hormones to generate social behaviors remain to be elucidated. We investigated whether some actions of androgen signaling in the control of social behavior may occur through the regulation of estradiol synthesis in the highly social cichlid fish, Astatotilapia burtoni. Specifically, we examined the expression of cyp19a1, a brain-specific aromatase, in the brains of male A. burtoni lacking a functional ARα gene (ar1), which was recently found to be necessary for aggression in this species. We found that cyp19a1 expression is higher in wild-type males compared to ar1 mutant males in the anterior tuberal nucleus (ATn), the putative fish homolog of the mammalian ventromedial hypothalamus, a brain region that is critical for aggression across taxa. Using in situ hybridization chain reaction, we determined that cyp19a1+ cells coexpress ar1 throughout the brain, including in the ATn. We speculate that ARα may modulate cyp19a1 expression in the ATn to govern aggression in A. burtoni. These studies provide novel insights into the hormonal mechanisms of social behavior in teleosts and lay a foundation for future functional studies.

Severe osmotic demyelination syndrome with cortical involvement in the context of severe hyponatremia and central diabetes insipidus: an uncommon presentation of an unusual combination.

BACKGROUND: Osmotic demyelination syndrome (ODS) with cerebral cortical involvement is a rare complication of severe hyponatremia correction. Careful management of hyponatremia is crucial, particularly in patients with risk factors, such as alcohol use disorder and diabetes insipidus. CASE: A patient in his 40s with a history of alcohol use disorder and central diabetes insipidus developed ODS after a 24 mEq/L osmolar increase during the treatment of hyponatremia. The patient's condition progressed into locked-in syndrome and then improved to spastic tetraparesis after cortical basal ganglia ODS improved. DISCUSSION: The differential diagnosis of cortical demyelination includes laminar cortical necrosis, being the interpretation of Apparent Diffusion Coefficient (ADC) MRI sequence is a useful tool.This case underscores the need to investigate and improve diagnosis and treatment strategies in patients with ODS. It also emphasises the significance of careful hyponatremia correction and frequent monitoring, particularly in patients with known risk factors for ODS.

New methods to investigate the GnRH pulse generator.

The exact neural construct underlying the dynamic secretion of gonadotrophin-releasing hormone (GnRH) has only recently been identified despite the detection of multiunit electrical activity volleys associated with pulsatile luteinising hormone (LH) secretion four decades ago. Since the discovery of kisspeptin/neurokinin B/dynorphin neurons in the mammalian hypothalamus, there has been much research into the role of this neuronal network in controlling the oscillatory secretion of gonadotrophin hormones. In this review, we provide an update of the progressive application of cutting-edge techniques combined with mathematical modelling by the neuroendocrine community, which are transforming the functional investigation of the GnRH pulse generator. Understanding the nature and function of the GnRH pulse generator can greatly inform a wide range of clinical studies investigating infertility treatments.