Social memory in female mice is rapidly modulated by 17ß-estradiol through ERK and Akt modulation of synapse formation.

Social memory is essential to the functioning of a social animal within a group. Estrogens can affect social memory too quickly for classical genomic mechanisms. Previously, 17ß-estradiol (E2) rapidly facilitated short-term social memory and increased nascent synapse formation, these synapses being potentiated following neuronal activity. However, what mechanisms underlie and coordinate the rapid facilitation of social memory and synaptogenesis are unclear. Here, the necessity of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling for rapid facilitation of short-term social memory and synaptogenesis was tested. Mice performed a short-term social memory task or were used as task-naïve controls. ERK and PI3K pathway inhibitors were infused intradorsal hippocampally 5 min before E2 infusion. Forty minutes following intrahippocampal E2 or vehicle administration, tissues were collected for quantification of glutamatergic synapse number in the CA1. Dorsal hippocampal E2 rapid facilitation of short-term social memory depended upon ERK and PI3K pathways. E2 increased glutamatergic synapse number (bassoon puncta positive for GluA1) in task-performing mice but decreased synapse number in task-naïve mice. Critically, ERK signaling was required for synapse formation/elimination in task-performing and task-naïve mice, whereas PI3K inhibition blocked synapse formation only in task-performing mice. While ERK and PI3K are both required for E2 facilitation of short-term social memory and synapse formation, only ERK is required for synapse elimination. This demonstrates previously unknown, bidirectional, rapid actions of E2 on brain and behavior and underscores the importance of estrogen signaling in the brain to social behavior.

Circadian Rhythms Tied to Changes in Brain Morphology in a Densely Sampled Male.

Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed 40 MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.

Diurnal Fluctuations in Steroid Hormones Tied to Variation in Intrinsic Functional Connectivity in a Densely Sampled Male.

Most of mammalian physiology is under the control of biological rhythms, including the endocrine system with time-varying hormone secretion. Precision neuroimaging studies provide unique insights into how the endocrine system dynamically regulates aspects of the human brain. Recently, we established estrogen's ability to drive widespread patterns of connectivity and enhance the global efficiency of large-scale brain networks in a woman sampled every 24 h across 30 consecutive days, capturing a complete menstrual cycle. Steroid hormone production also follows a pronounced sinusoidal pattern, with a peak in testosterone between 6 and 7 A.M. and nadir between 7 and 8 P.M. To capture the brain's response to diurnal changes in hormone production, we carried out a companion precision imaging study of a healthy adult man who completed MRI and venipuncture every 12-24 h across 30 consecutive days. Results confirmed robust diurnal fluctuations in testosterone, 17ß-estradiol-the primary form of estrogen-and cortisol. Standardized regression analyses revealed widespread associations between testosterone, estradiol, and cortisol concentrations and whole-brain patterns of coherence. In particular, functional connectivity in the Dorsal Attention Network was coupled with diurnally fluctuating hormones. Further, comparing dense-sampling datasets between a man and a naturally cycling woman revealed that fluctuations in sex hormones are tied to patterns of whole-brain coherence in both sexes and to a heightened degree in the male. Together, these findings enhance our understanding of steroid hormones as rapid neuromodulators and provide evidence that diurnal changes in steroid hormones are associated with patterns of whole-brain functional connectivity.

Small-molecule Ro-08-2750 interacts with many RNA-binding proteins and elicits MUSASHI2-independent phenotypes.

RNA-binding proteins (RBPs) are key regulators of gene expression. Small molecules targeting these RBP-RNA interactions are a rapidly emerging class of therapeutics for treating a variety of diseases. Ro-08-2750 (Ro) is a small molecule identified as a competitive inhibitor of Musashi (MSI)-RNA interactions. Here, we show that multiple Ro-dependent cellular phenotypes, specifically adrenocortical steroid production and cell viability, are Musashi-2 (MSI2)-independent. Using an unbiased proteome-wide approach, we discovered Ro broadly interacts with RBPs, many containing RRM domains. To confirm this finding, we leveraged the large-scale ENCODE data to identify a subset of RBPs whose depletion phenocopies Ro inhibition, indicating Ro is a promiscuous inhibitor of multiple RBPs. Consistent with broad disruption of ribonucleoprotein complexes, Ro treatment leads to stress granule formation. This strategy represents a generalizable framework for validating the specificity and identifying targets of RBP inhibitors in a cellular context.

Early-pregnancy sex steroid and thyroid function hormones, thyroid autoimmunity, and maternal papillary thyroid cancer incidence in the Finnish Maternity Cohort.

Thyroid cancer more commonly affects women than men and is the third most frequently diagnosed cancer among women of reproductive age. We conducted a nested case-control study within the Finnish Maternity Cohort to evaluate pre-diagnostic sex steroid and thyroid function markers in relation to subsequent maternal papillary thyroid cancer. Cases (n = 605) were women ages 18-44 years, who provided an early-pregnancy (<20 weeks gestation) blood sample and were diagnosed with papillary thyroid cancer up to 11 years afterward. Controls (n = 1185) were matched to cases 2:1 by gestational age, mother's age, and date at blood draw. Odds ratios (ORs) for the associations of serum thyroid peroxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), progesterone, and estradiol with papillary thyroid cancer were estimated using conditional logistic regression. TPO-Ab and Tg-Ab positivity (>95th percentile among controls) were associated with more than 3-fold (OR = 3.32, 95% confidence interval [CI] 2.33-4.72) and 2-fold (OR = 2.03, 95% CI 1.41-2.93) increased odds of papillary thyroid cancer, respectively. These associations were similar by time since blood draw, parity, gestational age, smoking status, and age and stage at diagnosis. In models excluding TPO-Ab or Tg-Ab positivity, TPO-Ab (quartile 4 vs. 1: OR = 1.66, 95% CI 1.17-2.37, p-trend = .002) and Tg-Ab (quartile 4 vs. 1: OR = 1.74, 95% CI 1.22-2.49, p-trend = .01) levels were positively associated with papillary thyroid cancer. No associations were observed for estradiol, progesterone, TSH, fT3, or fT4 overall. Our results suggest that thyroid autoimmunity in early pregnancy may increase the risk of maternal papillary thyroid cancer.

Combined perceptual and chemical analyses show no compelling evidence for ovulatory cycle shifts in women's axillary odour.

Although men's attraction to women's body odour has been suggested to vary over the ovulatory cycle, peaking around the fertile window, we still lack methodologically robust evidence corroborating this effect. Further, the chemical underpinnings of male preference for the odour of ovulating women remain unknown. Here, we combined perceptual and chemical analyses to investigate the axillary odour of naturally cycling women over 10 days, covering the gradual change in fertility across the ovulatory cycle with a focus on fertile days. The fertile state was confirmed by urinary ovulation tests as well as salivary oestradiol and progesterone levels. Men rated the scent of unfamiliar women, resembling a first encounter. We used multivariate analyses to relate variation in both odour ratings and chemical composition to female conception probability, temporal distance to ovulation and ovarian hormone levels. Our results provide no evidence that males prefer the odour of fertile women. Furthermore, the volatile analysis indicated no link between axillary odour composition and current fertility status. Together, our results showed no convincing support for a chemical fertility cue in women's axillary odour, questioning the presence of olfactory fertility information that is recognizable during first encounters in modern humans.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

Characteristics of bone mineral density in patients with functional hypothalamic amenorrhoea and its association with reproductive hormones and body composition.

OBJECTIVE: Bone mineral density (BMD) is typically reduced in patients with female athlete triad (FAT) and anorexia nervosa (AN). However, bone health in most patients with functional hypothalamic amenorrhoea (FHA), who may not suffer from severe energy deficiency, has not received adequate attention in clinical practice. This study aimed to investigate BMD and its association with clinical and endocrine features in individuals with FHA and to provide clinical evidence for improving bone loss and preventing osteoporosis in FHA. DESIGN: To assess the bone status of patients with FHA and investigate its association with various clinical and endocrinological characteristics. PATIENTS: We retrospectively analysed 80 patients with FHA who attended the Obstetrics and Gynecology Hospital of Fudan University from January 2022 to March 2023. MEASUREMENTS: The levels of reproductive hormones, including luteinising hormone (LH), follicle-stimulating hormone, oestradiol (E2 ) and total testosterone (TT), were examined at the time of initial diagnosis, and a body composition analyser was used to measure body fat percentage (BF%), lean body mass (LBM) and segmental muscle/fat. Dual-emission X-ray absorptiometry was used to measure lumbar spine BMD and femoral neck BMD in patients with FHA, and the Z score was calculated. RESULTS: The study cohort consisted of 80 female patients with FHA. The average age of the patients was 24.64 ± 6.02 years, and their body mass index (BMI) was 19.47 ± 2.86 kg/m2 . The duration of weight loss was 12 (6, 24) months, while the duration of oligo/amenorrhoea was 12 (4.5, 24) months. The mean degree of weight loss was 18.39 ± 9.53%. Low BMD were present in 15% of patients with FHA at the lumbar spine and/or femoral neck; 12.5% and 10% had low bone mass at the lumbar spine and femoral neck, respectively. The low bone mass group experienced a longer period of weight loss than the normal group [24 (16.5, 60) vs. 12 (4.5, 24) months, p = .037]. In addition, the abnormal group had a lower BMR (basal metabolic rate, BMR) [1158 ± 85 vs. 1231 ± 91 kcal/day, p = .011] and lower bone mineral content [2.15 ± 0.26 vs. 2.43 ± 0.31 kg, p = .009] than the normal group. Both LBMD and femoral neck BMD (Fn BMD) were positively correlated with BMI, BF%, LBM, and regional muscle/fat mass (all p < .05). There was also a positive correlation between LBMD and basal LH levels (p = .009) and waist-to-hip ratio (p = .034), whereas Fn BMD was positively correlated with TT levels (p = .029). Multiple linear regression analysis showed that LBM was positively associated with LBMD (ß = .007, 95% confidence interval [CI] = 0.004-0.009, p < .001), while trunk muscle mass was positively associated with Fn BMD (ß = .046, 95% CI = 0.013-0.080, p = .008). CONCLUSION: Fifteen percent of the patients with FHA exhibited low bone mass, a condition associated with prolonged weight loss. The basal LH and TT levels showed positive correlations with LBMD and Fn BMD, respectively. Meanwhile, BMR levels, BMI, BF%, and muscle mass were all positively correlated with LBMD and Fn BMD. Clinically, we should be attentive to suboptimal bone health in patients with FHA and take early screening, diagnosis and intervention measures, especially appropriate muscle mass gain, to prevent the onset of osteoporosis and fragility fractures in the long term.

The intrafollicular concentrations of biologically active cortisol in women rise abruptly shortly before ovulation and follicular rupture.

STUDY QUESTION: What is the temporal activity and the concentration in follicular fluid (FF) of the anti-inflammatory steroid cortisol during the ovulatory process in humans? SUMMARY ANSWER: Intrafollicular concentrations of cortisol become massively upregulated close to ovulation concomitant with an exceptionally high biological activity securing a timely and efficient termination of inflammatory processes. WHAT IS KNOWN ALREADY: Ovulation has been described as a local, controlled inflammatory process resulting in the degeneration of the follicle wall which facilitate oocyte extrusion. Ovulation also affects the glucocorticoid metabolism of granulosa cells (GCs) and although de novo synthesis of cortisol only occurs in the adrenal cortex, the mid-cycle surge has been shown to induce a change from high expression of HSD11B2, inactivating cortisol to cortisone, to high expression of HSD11B1 which reversibly catalyses cortisol production from cortisone. Furthermore, high concentrations of progesterone and 17OH-progesterone within follicles may cause dislodging of cortisol from cortisol binding protein (CBP) thereby activating the biological activity of cortisol. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 50 women undergoing fertility treatment according to a standard antagonist protocol at a university hospital-affiliated fertility clinic in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women donated FF and GCs from one follicle for research purpose aspirated at one of four time points during the process of final maturation of follicles: T = 0 h, T = 12 h, T = 17 h, T = 32 h. A second sample was collected at oocyte pick up at T = 36 h. The concentration of cortisol and cortisone together with a range of sex steroids was measured by LC-MS/MS in FF collected at the five time points mentioned above. Whole genome microarray data, validated by q-PCR analysis, was used to evaluate gene expression of CYP11B1, CYP21A2, HSD11B1, HSD11B2, and NR3C1 in GCs at the same time points. MAIN RESULTS AND THE ROLE OF CHANCE: The concentration of cortisol was significantly increased from a few nM at 0 h to around 100-140 nM (P ≤ 0.0001) at 32-36 h, whilst cortisone was almost constant from 0 to 17 h at a concentration of between 90 and 100 nM being significantly reduced to 25-40 nM (P ≤ 0.0001) at 32-36 h. This was paralleled by a 690-fold upregulation of HSD11B1 from 0 to 12 h increasing to a more than 20.000-fold change at 36 h. HSD11B2 was quickly downregulated 15- to 20-fold after ovulation induction. Concentrations of progesterone and 17OH-progesterone increased during the ovulatory process to high levels which in essence displaces cortisol from its binding protein CBP due to similar binding affinities. Furthermore, a significant decrease in 11-deoxycortisol expression was seen, but CYP11B1 expression was below detection limit in GCs. LIMITATIONS, REASONS FOR CAUTION: The study included women undergoing ovarian stimulation and results may differ from the natural cycle. More observations at each specific time point may have strengthened the conclusions. Furthermore, we have not been able to measure the actual active biological concentration of cortisol. WIDER IMPLICATIONS OF THE FINDINGS: For the first time, this study collectively evaluated the temporal pattern of cortisol and cortisone concentrations during human ovulation, rendering a physiological framework for understanding potential dysregulations in the inflammatory reaction of ovulation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the University Hospital of Copenhagen, Rigshospitalet, and Novo Nordisk Foundation grant number NNF21OC00700556. Interreg V ÔKS through ReproUnion (www.reprounion.eu); Region Zealand Research Foundation. The funders had no role in study design, collection of data, analyses, writing of the article, or the decision to submit it for publication. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

The Influence of Sex Hormones and X Chromosome in Immune Responses.

Males and females differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections and cancers. Cellular targets and molecular pathways underlying sexual dimorphism in immunity have started to emerge and appeared multifactorial. It became increasingly clear that sex-linked biological factors have important impact on the development, tissue maintenance and effector function acquisition of distinct immune cell populations, thereby regulating multiple layers of innate or adaptive immunity through distinct mechanisms. This review discusses the recent development in our understanding of the cell-intrinsic actions of biological factors linked to sex, sex hormones and sex chromosome complement, on immune cells, which may account for the sex differences in susceptibility to autoimmune diseases and allergies, and the sex-biased responses in natural immunity and cancer.

Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.

Genetic, Molecular, and Cellular Determinants of Sex-Specific Cardiovascular Traits.

Despite the well-known sex dimorphism in cardiovascular disease traits, the exact genetic, molecular, and cellular underpinnings of these differences are not well understood. A growing body of evidence currently points at the links between cardiovascular disease traits and the genome, epigenome, transcriptome, and metabolome. However, the sex-specific differences in these links remain largely unstudied due to challenges in bioinformatic methods, inadequate statistical power, analytic costs, and paucity of valid experimental models. This review article provides an overview of the literature on sex differences in genetic architecture, heritability, epigenetic changes, transcriptomic signatures, and metabolomic profiles in relation to cardiovascular disease traits. We also review the literature on the associations between sex hormones and cardiovascular disease traits and discuss the potential mechanisms underlying these associations, focusing on human studies.

Unraveling Hypothalamus-Pituitary dysregulation: Hypergonadotropism in F1 progeny due to prenatal exposure to hexavalent chromium.

The endocrine disruptor hexavalent chromium [Cr(VI)] is a proven reproductive toxicant. We recently demonstrated that prenatal Cr(VI) exposure causes testicular resistance to gonadotropins, resulting in hypergonadotropic hypoandrogenism in F1 rats. However, the mechanism driving hypergonadotropism in F1 rats exposed to Cr(VI) prenatally remains an enigma. Therefore, we hypothesized that 'Prenatal Cr(VI) exposure may disrupt steroid hormones-mediated negative feedback regulation of the hypothalamic GnRH, and its receptor in the pituitary of F1 rats, leading to hypergonadotropism.' We administered potassium dichromate (50, 100, or 200 mg/L) to pregnant rats through drinking water between days 9 and 14, and their male F1 offspring were euthanized at 60 days of age. Prenatal Cr(VI) exposure in F1 rats resulted in the accumulation of Cr in the hypothalamus and pituitary. Western blot detected decreased hypothalamic GnRH, Kisspeptin1, and its receptor GPR54, along with diminished ERα, AR, aromatase, and 5α reductase, and GnRH regulatory transcription factors Pit-1 and GATA-4 proteins. Immunohistochemical studies revealed increased immunopositivity of GnRH receptor, AR, 5α reductase, ERα, ERß, and aromatase proteins in the pituitary, whereas decreased Kisspeptin1, GPR54, and inhibin ß. Our findings imply that Cr(VI) exposure during the prenatal period disrupts the hypothalamic Kisspeptin-GPR54-Pit-1/GATA4-GnRH network, boosting the pituitary GnRH receptor. We conclude that prenatal exposure to Cr(VI) alters GnRH expression in the hypothalamus and its receptor in the pituitary of F1 progeny through interfering with the negative feedback effect of androgens and estrogens.

Early menarche and other endocrine disrupting effects of per- and polyfluoroalkyl substances (PFAS) in adolescents from Northern Norway. The Fit Futures study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) comprise a large group of chemicals that are ubiquitous in the environment and include recognized persistent organic pollutants. The aim of this cross-sectional study was to investigate possible endocrine disrupting effects of different PFAS in adolescents. METHODS: Serum concentrations of PFAS, thyroid, parathyroid and steroid hormones were measured in 921 adolescents aged 15-19 years in the Fit Futures study, Northern Norway. The questionnaire included data on self-reported age at menarche and puberty development score (PDS). Multiple linear and logistic regression analyses and principle component analyses (PCA) were used to assess associations of PFAS with hormones concentrations and puberty indices. RESULTS: In girls, total PFAS (∑PFAS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA) were positively associated with dehydroepiandrosterone sulfate (DHEAS) and negatively associated with 11-deoxycorticosterone (11-DOC)/DHEAS ratio. In boys, the associations with 11-DOC/DHEAS ratio were positive for ∑PFAS, perfluoroheptanoate (PFHpA), perfluoroheptane sulfonate (PFHpS), PFOA, and PFOS. Perfluoroundecanoate (PFUnDA) was negatively associated with free thyroxine (fT4) and free triiodothyronine (fT3) in boys. PFNA and PFDA were also negatively associated with fT3 in boys. Serum parathyroid hormone concentration (PTH) was negatively associated with ∑PFAS and perfluorohexane sulfonate (PFHxS) in girls, and with PFOS in boys. PFDA and PFUnDA were positively associated with early menarche, while ∑PFAS and PFOA were positively associated with PDS in boys. No associations of PFAS with serum testosterone, follicle-stimulating hormone, or luteinizing hormone were found in either sex. In girls, PFOA was positively associated with free testosterone index (FTI). In boys, PFOA was positively associated with androstendione and 17-OH-progesterone, while PFHpA was positively associated with estradiol. CONCLUSIONS: Serum concentrations of several PFAS were associated with parathyroid and steroid hormones in both sexes, and with thyroid hormones in boys, as well as with early menarche in girls and higher PDS in boys.

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.

Discriminatory Value of Steroid Hormones on Polycystic Ovary Syndrome and Clustering of Hyperandrogenism and Metabolic Factors.

OBJECTIVE: We determined (1) if 11-oxygenated androgens better identify polycystic ovary syndrome (PCOS) diagnosis in women with obesity compared to total or free testosterone (T) and free androgen index; (2) how biochemical hyperandrogenism and metabolic factors cluster in a cohort of women with infertility and obesity. METHODS: Women with obesity and PCOS comprised the study group (N = 132). Ovulatory women with obesity and idiopathic, tubal or male factor infertility were the control group (N = 83). Steroid hormones were measured by means of liquid chromatography tandem mass spectrometry. Receiver operating characteristic curves and principal component analysis were used. RESULTS: Women with obesity and PCOS had higher 11-ketotestosterone (11 KT) (1.22 nmol/L [0.84; 1.65] vs 1.05 [0.78; 1.35], P = .04) compared to controls, but not 11ß-hydroxyandrostenedione 4.30 [2.87; 5.92] vs 4.06 [3.22; 5.73], P = .44). 11-ketotestosterone (area under the curve: 0.59) did not better discriminate PCOS in women with obesity compared to: total T (0.84), free T (0.91), and free androgen index (0.85). We identified 4 principal components (PCs) in the PCOS group (72.1% explained variance): (1) insulin resistance status; (2) blood pressure; (3) obesity; (4) androgen status and 4 PCs in the control group (68.7% explained variance) with variables representing metabolism being dispersed in component 2, 3, and 4. CONCLUSIONS: Eleven-oxygenated androgens do not aid in the diagnosis of PCOS in women with obesity. Insulin resistance is the strongest PC in the PCOS group. There is no major dominant characteristic that defines obese non-PCOS women.

A phylogenetics-based nomenclature system for steroid receptors in teleost fishes.

Teleost fishes have emerged as tractable models for studying the neuroendocrine regulation of social behavior via molecular genetic techniques, such as CRISPR/Cas9 gene editing. Moreover, teleosts provide an opportunity to investigate the evolution of steroid receptors and their functions, as species within this lineage possess novel steroid receptor paralogs that resulted from a teleost-specific whole genome duplication. Although teleost fishes have grown in popularity as models for behavioral neuroendocrinology, there is not a consistent nomenclature system for steroid receptors and their genes, which may impede a clear understanding of steroid receptor paralogs and their functions. Here, we used a phylogenetic approach to assess the relatedness of protein sequences encoding steroid receptor paralogs in 18 species from 12 different orders of the Infraclass Teleostei. While most similarly named sequences grouped based on the established phylogeny of the teleost lineage, our analysis revealed several inconsistencies in the nomenclature of steroid receptor paralogs, particularly for sequences encoding estrogen receptor beta (ERß). Based on our results, we propose a nomenclature system for teleosts in which Greek symbols refer to proteins and numbers refer to genes encoding different subtypes of steroid receptors within the five major groups of this nuclear receptor subfamily. Collectively, our results bridge a critical gap by providing a cohesive naming system for steroid receptors in teleost fishes, which will serve to improve communication, promote collaboration, and enhance our understanding of the evolution and function of steroid receptors across vertebrates.

Evaluation of fish pituitary spheroids to study annual endocrine reproductive control.

The pituitary gland is a small endocrine gland located below the hypothalamus. This gland releases several important hormones and controls the function of many other endocrine system glands to release hormones. Fish pituitary hormonal cells are controlled by neuroendocrine and sex steroid feedback. To study the complex pituitary function in vivo, we established an in vitro pituitary spheroid assay and evaluated its suitability for monitoring the annual reproductive physiological conditions in Takifugu rubripes, also known as torafugu, is one of the most economically important species distributed in the northwestern part of the Pacific Ocean, in the western part of the East China Sea, and in more northern areas near Hokkaido, Japan. Fish pituitary spheroids can be easily constructed in liquid or solid plates. The culture medium (L-15) made the aggregation faster than MEM (Hank's). A Rho-kinase inhibitor (Y-27632, 10 µM) and/or fish serum (2.5 %) also promoted spheroid formation. Laser confocal microscopy analysis of spheroids cultured with annual serum of both sexes revealed that luteinizing hormone (LH) synthesis has the highest peak in the final maturation stage (3 years old, May) in accordance with the highest serum sex steroid levels; in contrast, follicle stimulating hormone (FSH) synthesis has no correlation with the dose of serum or nutrients. Similarly, 3D cell propagation assays using female serum showed that total pituitary cells displayed the highest proliferation at puberty onset (2 years old, October) before half a year of the spawning season. These results indicate that pituitary spheroids are useful in vitro models for monitoring the reproductive physiological status of fish in vivo and may be applicable to the in vitro screening of environmental chemicals and bioactive compounds affecting reproductive efficiency in aquaculture.

Sex and disease severity-based analysis of steroid hormones in ME/CFS.

PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by persistent fatigue and decreased daily activity following physical and/or cognitive exertion. While ME/CFS affects both sexes, there is a higher prevalence in women. However, studies evaluating this sex-related bias are limited. METHODS: Circulating steroid hormones, including mineralocorticoids (aldosterone), glucocorticoids (cortisol, corticosterone, 11-deoxycortisol, cortisone), androgens (androstenedione, testosterone), and progestins (progesterone, 17α-hydroxyprogesterone), were measured in plasma samples using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Samples were obtained from mild/moderate (ME/CFSmm; females, n=20; males, n=8), severely affected patients (ME/CFSsa; females, n=24; males, n=6), and healthy controls (HC, females, n=12; males, n=17). RESULTS: After correction for multiple testing, we observed that circulating levels of 11-deoxycortisol, 17α-hydroxyprogesterone in females, and progesterone in males were significantly different between HC, ME/CFSmm, and ME/CFSsa. Comparing two independent groups, we found that female ME/CFSsa had higher levels of 11-deoxycortisol (vs. HC and ME/CFSmm) and 17α-hydroxyprogesterone (vs. HC). In addition, female ME/CFSmm showed a significant increase in progesterone levels compared to HC. In contrast, our study found that male ME/CFSmm had lower circulating levels of cortisol and corticosterone, while progesterone levels were elevated compared to HC. In addition to these univariate analyses, our correlational and multivariate approaches identified differential associations between our study groups. Also, using two-component partial least squares discriminant analysis (PLS-DA), we were able to discriminate ME/CFS from HC with an accuracy of 0.712 and 0.846 for females and males, respectively. CONCLUSION: Our findings suggest the potential value of including steroid hormones in future studies aimed at improving stratification in ME/CFS. Additionally, our results provide new perspectives to explore the clinical relevance of these differences within specific patient subgroups.

Prolactin as an adrenocorticotropic hormone: Prolactin signalling is a conserved key regulator of sexually dimorphic adrenal gland function in health and disease.

A large number of previous reports described an effect of the pituitary hormone prolactin (PRL) on steroid hormone production by the adrenal cortex. However, those studies remained anecdotal and were never converted into a conceptual and mechanistic framework, let alone being translated into clinical care. In the light of our recently published landmark study where we described PRL signalling as a pivotal regulator of the sexually dimorphic adrenal phenotype in mouse and of adrenal androgen production in humans, we present here the overarching hypothesis that PRL signalling increases the activity of Steroidogenic Factor-1 (SF-1/NR5A1), a transcription factor that has an essential role in adrenal gland development and function, to regulate adrenal cortex growth and hormonal production in physiological and pathological conditions. PRL can then be considered as a bona fide adrenocorticotropic hormone synergizing with ACTH in the endocrine control of adrenal cortex function.