Oxytocin can regulate immunological activity directly or indirectly; however, immunological functions and mechanisms of oxytocin actions under chronic stress like cesarean delivery (CD) are poorly understood. Our study found that abnormal oxytocin production and secretion in CD rats caused atrophy of thymic tissues. Neurotoxin kainic acid microinjected into the dorsolateral supraoptic nucleus in male rats selectively reduced hypothalamic oxytocin levels, increased corticotrophin-releasing hormone and plasma interleukin-1β while reducing plasma oxytocin, thyroxine and testosterone levels and causing atrophy of immune tissues. Thus, plasma oxytocin is essential for immunological homeostasis, which involves oxytocin facilitation of thyroid hormone and sex steroid secretion.

Kisspeptins are essential regulators of the reproductive axis, with capacity to potently activate gonadotropin-releasing hormone neurons, acting also as central conduits for the metabolic regulation of fertility. Recent evidence suggests that kisspeptins per se may also modulate several metabolic parameters, including body weight, food intake or energy expenditure, but their actual roles and site(s) of action remain unclear. We present herein a series of studies addressing the metabolic effects of central and peripheral administration of kisspeptin-10 (Kp-10; 1 nmol and 3 nmol daily, respectively) for 11 days in mice of both sexes. To assess direct metabolic actions of Kp-10 versus those derived indirectly from its capacity to modulate gonadal hormone secretion, kisspeptin effects were tested in adult male and female mice gonadectomized and supplemented with fixed, physiological doses of testosterone or 17β-estradiol, respectively. Central administration of Kp-10 decreased food intake in male mice, especially during the dark phase (~50%), which was accompanied by a reduction in total and nocturnal energy expenditure (~16%) and locomotor activity (~70%). In contrast, opposite patterns were detected in female mice, with an increase in total and nocturnal locomotor activity (>65%), despite no changes in food intake or energy expenditure. These changes were independent of body weight, as no differences were detected in mice of both sexes at the end of Kp-10 treatments. Peripheral administration of Kp-10 failed to alter any of the metabolic parameters analyzed, except for a decrease in locomotor activity in male mice and a subtle increase in 24 h food intake in female mice, denoting a predominant central role of kisspeptins in the control of energy metabolism. Finally, glucose tolerance and insulin sensitivity were not significantly affected by central or peripheral treatment with Kp-10. In conclusion, our data reveal a potential role of kisspeptins in the control of key metabolic parameters, including food intake, energy expenditure and locomotor activity, with a preferential action at central level, which is sex steroid-independent but sexually dimorphic.

BACKGROUND: The decrease in serum estrogens after menopause is associated with a shift from a gynoid to an android adipose tissue (AT) distribution. Menopausal hormone therapy (HT) mitigates this change and accompanying metabolic dysfunction, but its effects on AT sex steroid metabolism have not been characterized.
OBJECTIVE: We studied effects of HT on subcutaneous and visceral AT estrogen and androgen concentrations and metabolism in postmenopausal women.
METHODS: Serum and subcutaneous and visceral AT from 63 postmenopausal women with (n=50) and without (n=13) per oral HT were analyzed for estrone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone, and serum estrone sulfate using liquid chromatography-tandem mass spectrometry. Steroid sulfatase activity was measured using radiolabeled precursors. mRNA expression of genes encoding sex steroid-metabolizing enzymes and receptors was performed using real-time reverse transcription quantitative polymerase chain reaction.
RESULTS: HT users had 4- to 7-fold higher concentrations of estrone and estradiol in subcutaneous and visceral AT, and 30% lower testosterone in visceral AT compared to non-users. Estrogen-to-androgen ratios were 4- to 12-fold higher in AT of users compared to non-users of HT. In visceral AT, estrogen-to-androgen ratios increased with HT estradiol dose. AT to serum ratios of estrone and estradiol remained high in HT users.
CONCLUSIONS: Higher local estrogen to androgen ratios and high AT to serum ratios of estrogen concentrations in HT users suggest that HT may significantly influence intracrine sex steroid metabolism in AT, and these local changes could be involved in the preventive effect of HT on menopause-associated abdominal adiposity.

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 ERβ. The aim of this review is to summarize the genetic studies that have been undertaken to comprehend the specific contribution of ERα and ERβ 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.

The red spotted grouper Epinephelus akaara is a marine species of economic importance and also at risk of extinction. This study investigated the effects of high water temperature on the growth and maturation of juvenile E. akaara females. From 160-420 days post-hatching (dph), the fish were maintained under natural water temperature (NT) and a constant high-water temperature (HT). From 240 dph, both the total length and body weight in the HT group were greater than in NT group. After 360 dph, the gonadosomatic index was also increased in the HT group compared to NT group. Mature oocytes were only observed in the HT group at 330, 360, and 390 dph. Both kiss1 and kiss2 levels increased at 240 and 270 dph in both groups; however, they were greater in the HT group at 240 dph. Similarly, gpr54 levels after 360 dph were greater in the HT group, suggesting that kisspeptin is related to maturation via its receptor gpr54. Levels of fshβ and lhβ were greater in the HT group after 360 dph. Estradiol-17β (E2) levels after 160 dph (except 300 dph) were greater in the HT group than in the NT group, suggesting that the higher E2 levels trigger maturation, and is related to increased fshβ and lhβ. This study provides evidence that high water temperature is effective in accelerating growth and triggering early maturation of juvenile E. akaara, via regulating gpr54, fshβ, lhβ, and E2 levels.

Epilepsy, is a serious neurological condition, characterized by recurring, unprovoked seizures and affects over 50 million people worldwide. Epilepsy has an equal prevalence in males and females, and occurs throughout the life span. Women with epilepsy (WWE) present with unique challenges due to the cyclical fluctuation of sex steroid hormone concentrations during their life course. These shifts in sex steroid hormones and their metabolites are intricately intertwined with seizure susceptibility and affect epilepsy during the life course of women in a complex manner. Here we present a review encompassing neurosteroids-steroids that act on the brain regardless of their site of synthesis in the body; the role of neurosteroids in women with epilepsy through their life-course; exogenous neurosteroid trials; and future research directions. The focus of this review is on progesterone and its derived neurosteroids, given the extensive basic research that supports their role in modulating neuronal excitability.

MafB is a transcription factor that regulates macrophage differentiation. Macrophages are a traditional feature of the hamster Harderian gland (HG); however, studies pertaining to MafB expression in the HG are scant. Here, the full-length cDNA of the MafB gene in hamsters was cloned and sequenced. Molecular characterization revealed that MafB encodes a protein containing 323 amino acids with a DNA-binding domain, a transactivation domain, and a leucine zipper domain. qPCR assays indicated that MafB was expressed in different tissues of both sexes. The highest relative expression levels in endocrine tissues were identified in the pancreas. Gonadectomy in male hamsters was associated with significantly higher mRNA levels in the HG; replacement with dihydrotestosterone restored mRNA expression. The HG in male hamsters contained twofold more MafB mRNA than the HG of female hamsters. Adrenals revealed similar mRNA relative expression levels during the estrous cycle. The estrous phase was associated with higher mRNA levels in the ovary. A significantly up-regulated expression and sexual dimorphism of MafB was found in the pancreas. Therefore, MafB in the HG may play an active role in the macrophage differentiation required for phagocytosis activity and intraocular repair. Additionally, sex steroids appear to strongly influence the MafB expression in the HG and pancreas. These studies highlight the probable biological importance of MafB in immunological defense and pancreatic β cell regulation.

BACKGROUND: Androgen insensitivity syndrome (AIS) is a common condition among individuals with differences of sexual development (DSD) and results from germline allelic variants in the androgen receptor (AR) gene. Understanding the phenotypic consequences of AR allelic variants that disrupt the activation function 2 (AF2) region is essential to grasping its clinical significance.
OBJECTIVE: This study aims to provide insights into the phenotypic characteristics and clinical impact of AR mutations affecting the AF2 region in AIS patients. We achieve this by reviewing reported AR variants in the AF2 region among individuals with AIS, including identifying a new phenotype associated with the c.2138T>C variant (p.Leu713Pro) in the AR gene.
METHODS: We comprehensively reviewed AR variants within the AF2 region reported in AIS and applied molecular dynamics simulations to assess the impact of the p.Leu713Pro variant on protein dynamics.
RESULTS: Our review of reported AR variants in the AF2 region revealed a spectrum of phenotypic outcomes in AIS patients. Molecular dynamics simulations indicated that the p.Leu713Pro variant significantly alters the local dynamics of the AR protein and disrupts the correlation and covariance between variables.
CONCLUSIONS: The diverse phenotypic presentations observed among individuals with AR variants in the AF2 region highlight the complexity of AIS. The altered protein dynamics resulting from the p.Leu713Pro variant further emphasize the importance of the AF2 region in AR function.
CONCLUSIONS: Our study provides valuable insights into AR mutations\' phenotypic characteristics and clinical impact on the AF2 region in AIS. Moreover, the disruption of protein dynamics underscores the significance of the AF2 region in AR function and its role in the pathogenesis of AIS.

Sexual maturation of Atlantic salmon males is marked by dramatic endocrine changes and rapid growth of the testes, resulting in an increase in the gonad somatic index (GSI). We examined the association of gonadal growth with serum sex steroids, as well as pituitary and testicular gene expression levels, which were assessed with a DNA oligonucleotide microarray. The testes transcriptome was stable in males with a GSI < 0.08% despite the large difference between the smallest and the largest gonads. Fish with a GSI ≥ 0.23% had 7-17 times higher serum levels of five male steroids and a 2-fold increase in progesterone, without a change in cortisol and related steroids. The pituitary transcriptome showed an upregulation of the hormone-coding genes that control reproduction and behavior, and structural rearrangement was indicated by the genes involved in synaptic transmission and the differentiation of neurons. The observed changes in the abundance of testicular transcripts were caused by the regulation of transcription and/or disproportional growth, with a greater increase in the germinative compartment. As these factors could not be separated, the transcriptome results are presented as higher or lower specific activities (HSA and LSA). LSA was observed in 4268 genes, including many genes involved in various immune responses and developmental processes. LSA also included genes with roles in female reproduction, germinal cell maintenance and gonad development, responses to endocrine and neural regulation, and the biosynthesis of sex steroids. Two functional groups prevailed among HSA: structure and activity of the cilia (95 genes) and meiosis (34 genes). The puberty of A. salmon testis is marked by the predominance of spermatogenesis, which displaces other processes; masculinization; and the weakening of external regulation. Results confirmed the known roles of many genes involved in reproduction and pointed to uncharacterized genes that deserve attention as possible regulators of sexual maturation.

BACKGROUND: Sexual dimorphism significantly influences cancer incidence and prognosis. Notably, females exhibit a lower risk and favorable prognosis for non-reproductive cancers compared to males, a pattern observable beyond the scope of risk behaviors such as alcohol consumption and smoking. Colorectal cancer, ranking third in global prevalence and second in mortality, disproportionately affects men. Sex steroid hormones, particularly estrogens and androgens, play crucial roles in cancer progression, considering epidemiological in vivo and in vitro, in general estrogens imparting a protective effect in females and androgens correlating with an increasing risk of colorectal cancer development.
METHODS: The hormonal impact on immune response is mediated by receptor interactions, resulting in heightened inflammation, modulation of NF-kB, and fostering an environment conducive to cancer progression and metastasis. These molecules also influence the enteric nervous system, that is a pivotal in neuromodulator release and intestinal neuron stimulation, also contributes to cancer development, as evidenced by nerve infiltration into tumors. Microbiota diversity further intersects with immune, hormonal, and neural mechanisms, influencing colorectal cancer dynamics. A comprehensive understanding of hormonal influences on colorectal cancer progression, coupled with the complex interplay between immune responses, microbiota diversity and neurotransmitter imbalances, underpins the development of more targeted and effective therapies.
CONCLUSIONS: Estrogens mitigate colorectal cancer risk by modulating anti-tumor immune responses, enhancing microbial diversity, and curbing the pro-tumor actions of the sympathetic and enteric nervous systems. Conversely, androgens escalate tumor growth by dampening anti-tumor immune activity, reducing microbial diversity, and facilitating the release of tumor-promoting factors by the nervous system. These findings hold significant potential for the strategic purposing of drugs to fine-tune the extensive impacts of sex hormones within the tumor microenvironment, promising advancements in colorectal cancer therapies.