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In mice, the uterus undergoes dynamic changes regulated by estrogen and progesterone during the estrous cycle. Proper regulation of these changes is critical for successful pregnancy. The Family with sequence similarity 3 (Fam3) gene family, comprising , , , and , encodes cytokine-like proteins, but their uterine roles remain unclear. This study examined Fam3 expression in the mouse uterus across the estrous cycle and assessed estrogen-dependent regulation. RNA-seq analysis revealed increased , , and expression during proestrus and estrus. Notably, showed dynamic regulation, peaking in these stages. To test estrogen regulation, estradiol was administered to ovariectomized mice, showing maximal expression at 24 h post-injection. ERα antagonist treatment blocked this induction, indicating ERα-mediated regulation. Immunofluorescence localized FAM3D to the cytoplasm of luminal and glandular epithelia, especially in the apical region, with no stromal or nuclear expression. These findings suggest that estrogen and Erα (Estrogen receptor alpha) signaling control Fam3d expression, implicating FAM3D in uterine epithelial function. This study provides novel insights into 's role in uterine physiology and a foundation for exploring its function in reproduction.

17-Beta-estradiol (E2) stimulates neural plasticity and dopaminergic transmission in the prefrontal cortex, which is critically involved in attentional control, working memory, and other executive functions. Studies investigating E2’s actions on prefrontally mediated behavior in the course of the menstrual cycle or during hormone replacement therapy are inconclusive, with numerous null findings as well as beneficial and detrimental effects. The current study focused on the effect of E2 on attentional performance, as animal studies indicate that supraphysiological doses (i.e., above estrous cycle levels) of E2 have beneficial effects on measures of attention in female rodents. To translate these findings to humans, we administered 12 mg E2-valerate or placebo orally to 34 naturally cycling women in the low-hormone early follicular phase using a randomized, double-blinded, pre-post design. Behavioral performance was tested twice during baseline and E2 peak, where E2 levels reached mildly supraphysiological levels in the E2 group. Aside from mainly prefrontally mediated tasks of attention, working memory, and other executive functions, we employed tasks of affectively modulated attention, emotion recognition, and verbal memory. E2 administration had a significant, but subtle negative impact on general processing speed and working memory performance. These effects could be related to an overstimulation of dopaminergic transmission. The negative effect of supraphysiological E2 on working memory connects well to animal literature. There were no effects on attentional performance or any other measure. This could be explained by different E2 levels being optimal for changing behavioral performance in specific tasks, which likely depends on the brain regions involved.

Iodoacetic acid (IAA) is a water disinfection byproduct that is an ovarian toxicant in vitro. However, information on the effects of IAA on ovarian function in vivo was limited. Thus, we determined whether IAA exposure affects estrous cyclicity, steroidogenesis, and ovarian gene expression in mice. Adult CD-1 mice were dosed with water or IAA (0.5–500 mg/L) in the drinking water for 35–40 days during which estrous cyclicity was monitored for 14 days. Ovaries were analyzed for expression of apoptotic factors, cell cycle regulators, steroidogenic factors, estrogen receptors, oxidative stress markers, and a proliferation marker. Sera were collected to measure pregnenolone, androstenedione, testosterone, estradiol, inhibin B, and follicle-stimulating hormone (FSH) levels. IAA exposure decreased the time that the mice spent in proestrus compared to control. IAA exposure decreased expression of the proapoptotic factor Bok and the cell cycle regulator Ccnd2 compared to control. IAA exposure increased expression of the proapoptotic factors Bax and Aimf1, the antiapoptotic factor Bcl2l10, the cell cycle regulators Ccna2, Ccnb1, Ccne1, and Cdk4, and estrogen receptor Esr1 compared to control. IAA exposure decreased expression of Sod1 and increased expression of Cat, Gpx and Nrf2. IAA exposure did not affect expression of Star, Cyp11a1, Cyp17a1, Hsd17b1, Hsd3b1, Esr2, or Ki67 compared to control. IAA exposure decreased estradiol levels, but did not alter other hormone levels compared to control. In conclusion, IAA exposure alters estrous cyclicity, ovarian gene expression, and estradiol levels in mice. Summary sentence IAA exposure alters estrous cyclicity, ovarian gene expression, and estradiol levels in mice. Graphical Abstract

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development 1 . The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure 2 . Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R , including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation. MC3R deficiency is associated with a delay in the onset of puberty, and a reduction in growth and lean mass.

Abstract Context The ideal therapy for endometriosis (EM) and uterine fibroids (UFs) would suppress estrogenic drive to the endometrium and myometrium, while minimizing vasomotor symptoms and bone loss associated with current treatments. An integrated neurokinin-kisspeptin system involving substance P and neurokinin B acting at the neurokinin (NK) receptors 1 and 3, respectively, modulates reproductive hormone secretion and represents a therapeutic target. Objective This work aimed to assess the effects of the novel NK1,3 antagonist elinzanetant on reproductive hormone levels in healthy women. Methods A randomized, single-blinded, placebo-controlled study was conducted in 33 women who attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3 or 4, 9 or 10, 15 or 16, and 21 or 22 to measure serum reproductive hormones. In cycle 2, women were randomly assigned to receive once-daily oral elinzanetant 40, 80, 120 mg, or placebo (N = 8 or 9 per group). Results Elinzanetant dose-dependently lowered serum luteinizing hormone, estradiol (120 mg median change across cycle: –141.4 pmol/L, P = .038), and luteal-phase progesterone (120 mg change from baseline on day 21 or 22: –19.400 nmol/L, P = .046). Elinzanetant 120 mg prolonged the cycle length by median of 7.0 days (P = .023). Elinzanetant reduced the proportion of women with a luteal-phase serum progesterone concentration greater than 30 nmol/L (a concentration consistent with ovulation) in a dose-related manner in cycle 2 (P = .002). Treatment did not produce vasomotor symptoms. Conclusion NK1,3 receptor antagonism with elinzanetant dose-dependently suppressed the reproductive axis in healthy women, with the 120-mg dose lowering estradiol to potentially ideal levels for UFs and EM. As such, elinzanetant may represent a novel therapy to manipulate reproductive hormone levels in women with hormone-driven disorders.

Inflammatory pain is a key component of acute traumatic pain and chronic rheumatic disease, which significantly reduces the quality of life of those who suffer from it and is often refractory to treatment. One contributor to the failure of current treatments is that the majority of pain testing has historically been performed in male subjects while the majority of pain patients are women. To better manage inflammatory pain, first the baseline sex differences in its experience must be assessed. Therefore, we evaluated C57BL/6J male and female mice for baseline sex differences in the formalin model of inflammatory pain, further investigating the observed significant sex differences through both assessing female mice at each phase of the estrous cycle and through examining the effects of gonadectomy (ovariectomy or castration) within the formalin model of inflammatory pain. Female mice in the metestrus or diestrus phase had decreased inflammatory pain relative to both male mice and female mice in the proestrus or estrus phase. Ovariectomy resulted in decreased pain, which was restored through treatment with estradiol (E2). Castration similarly reduced pain in male mice. Injection of the G-protein coupled estrogen receptor (GPER) agonist G1 resulted in significant antinociception in both female and male mice, in both mice that had received sham surgery or gonadectomy. These results establish baseline sex differences in the formalin model of inflammatory pain and support the need for further investigation into the interaction between estrogen, its receptors, and testosterone in the regulation of nociception.

Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in women of reproductive age. It is difficult to treat PCOS because of its complex etiology and pathogenesis. Here, we characterized the roles of gut microbiota on the pathogenesis and treatments in letrozole (a nonsteroidal aromatase inhibitor) induced PCOS rat model. Changes in estrous cycles, hormonal levels, ovarian morphology and gut microbiota by PCR-DGGE and real-time PCR were determined. The results showed that PCOS rats displayed abnormal estrous cycles with increasing androgen biosynthesis and exhibited multiple large cysts with diminished granulosa layers in ovarian tissues. Meanwhile, the composition of gut microbiota in letrozole-treated rats was different from that in the controls. Lactobacillus, Ruminococcus and Clostridium were lower while Prevotella was higher in PCOS rats when compared with control rats. After treating PCOS rats with Lactobacillus and fecal microbiota transplantation (FMT) from healthy rats, it was found that the estrous cycles were improved in all 8 rats in FMT group, and in 6 of the 8 rats in Lactobacillus transplantation group with decreasing androgen biosynthesis. Their ovarian morphologies normalized. The composition of gut microbiota restored in both FMT and Lactobacillus treated groups with increasing of Lactobacillus and Clostridium, and decreasing of Prevotella. These results indicated that dysbiosis of gut microbiota was associated with the pathogenesis of PCOS. Microbiota interventions through FMT and Lactobacillus transplantation were beneficial for the treatments of PCOS rats.

RationaleSome mood disorders, such as major depressive disorder, are more prevalent in women than in men. However, historically preclinical studies in rodents have a lower inclusion rate of females than males, possibly due to the fact that behavior can be affected by the estrous cycle. Several studies have demonstrated that chronic antidepressant treatment can decrease anxiety-associated behaviors and increase adult hippocampal neurogenesis in male rodents.ObjectiveVery few studies have looked at the effects of antidepressants on behavior and neurogenesis across the estrous cycle in naturally cycling female rodents.MethodsHere, we analyze the effects of chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac) on behavior and adult hippocampal neurogenesis in naturally cycling C57BL/6J females across all four phases of the estrous cycle.ResultsIn naturally cycling C57BL/6J females, fluoxetine decreases negative valence behaviors associated with anxiety in the elevated plus maze and novelty-suppressed feeding task, reduces immobility time in forced swim test, and increases adult hippocampal neurogenesis. Interestingly, the effects of fluoxetine on several negative valence behavior and adult hippocampal neurogenesis measures were mainly found within the estrus and diestrus phases of the estrous cycle.ConclusionsTaken together, these data are the first to illustrate the effects of fluoxetine on behavior and adult hippocampal neurogenesis across all four phases of the murine estrous cycle.

Ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3), a plasma membrane-bound metabolic enzyme, converts extracellular nucleotides into nucleosides. ENTPD3 is involved in various pathophysiological processes, including cellular adhesion, metabolism, activation, and migration. However, its specific function in the uterus remains unclear. This study aimed to investigate the expression pattern and localization of Entpd3 in the mouse uterus throughout the estrous cycle using immunohistochemistry (IHC), quantitative real-time PCR, and western blot analysis. The effect of sex steroid hormones on Entpd3 expression was also examined in ovariectomized (OVX) mice treated with 17β-estradiol (E2)/progesterone (P4) and estrogen receptor antagonist (Fulvestrant)/progesterone receptor antagonist (Mifepristone). Results demonstrated that elevated levels of Entpd3 mRNA and protein were noted during estrus and metestrus, with a decline in diestrus and proestrus. IHC revealed abundant ENTPD3 in the cytoplasm of glandular and luminal epithelial cells during estrus and metestrus. Additionally, treatment with E2 or P4 in OVX mice downregulated the expression of Entpd3 in the mouse uterus, which was rescued by Fulvestrant or Mifepristone. This study demonstrated that the expression of Entpd3 in the mouse uterus varied dynamically throughout the estrous cycle and was steroid-dependent, suggesting a potential role for Entpd3 in female mice’s reproductive function.

Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARH and Kiss1AVPV neurons. In agreement with this finding, Kiss1ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons.