Estrogen deficiency affects synchronized neural connectivity in the olfactory bulb-nucleus accumbens circuit: A local field potential study in ovariectomized mouse model.

Estrogen plays a crucial role in regulating various brain functions, including cognitive, emotional, and social behaviors. Menopausal women face a decline in estrogen levels, which has been linked to several physical and mental health issues. However, the impact of estrogen on the olfactory bulb-nucleus accumbens (OB-NAc) circuit, which is essential for regulating emotions and cognitive behaviors, remains poorly understood. To test the hypothesis that estrogen deficiency affects signal processing, we recorded local field potentials (LFPs) using intracranial electrodes implanted in four-week-old ovariectomized (OVX) mice during an open-field test (OFT). The results showed a decrease in locomotor activity and increase in anxiety-like behaviors in OVX mice. Furthermore, we found a decrease in high-gamma power in the OB. We analyzed coherence and inter-region phase-amplitude coupling (ir-PAC) to explore the connectivity between the OB and NAc. We observed a decrease in low-gamma and high-gamma coherence in OVX mice. Additionally, we found that the direction of connectivity from the NAc to the OB was disrupted in OVX mice. In summary, our study provides evidence that estrogen deficiency is linked to synchronized neural connectivity changes in the OB-NAc circuit. These findings have implications for our understanding of the roles played by the OB-NAc neural circuit and estrogen in the regulation of general exploratory behavior and anxiety-like behavior.

Alleviation of Menopausal Symptoms by Yam (Dioscorea japonica Thunb.) and Gromwell (Lithospermum erythrorhizon Sieb. Et Zucc.) Extracts in Ovariectomized Mice.

SCOPE: The decline in estrogen during menopause contributes to a variety of menopausal symptoms, for which hormone replacement therapy (HRT) has been extensively applied. Regarding side effects and limited effectiveness of HRT for specific individuals, there is a growing interest in safe alternatives such as phytoestrogens which are structurally analogous to estrogens. This study aims to investigate the efficacy of yam and gromwell extracts, rich in bioactive compounds, and the synergistic effect of extracts on symptoms induced by estrogen deficiency in ovariectomized (OVX) mice. METHODS AND RESULTS: OVX mice receive dietary intervention of either yam, gromwell extract, or their mixture for 14 weeks. Sham-operated mice and E2-injected OVX mice serve as positive controls. Following 14 weeks of oral administration, blood, adipose tissue, vagina, uterus, femurs, and tibias are harvested for further investigation. Consequently, yam and gromwell extracts ameliorate menopausal conditions such as weight gain, glucose intolerance, dyslipidemia, and osteoporosis in estrogen-deficient OVX mice. In addition, the mixture of yam and gromwell extracts synergistically aids in the relief of the indications. CONCLUSION: These results indicate the potential use of yam and gromwell extracts, as well as their mixture, for the development of healthy functional foods to modulate menopausal symptoms.

Grape seed extract prevents oestrogen deficiency-induced bone loss by modulating the gut microbiota and metabolites.

Proanthocyanidin-rich grape seed extract (GSE) has been shown to have the potential to protect bones, although the underlying mechanism remains unknown. The current study aims to explore GSE's preventive and therapeutic impact on bone loss induced by oestrogen deficiency and the underlying mechanism through the gut microbiota (GM) and metabolomic responses. In oestrogen-deficient ovariectomized (OVX) mice, GSE ameliorated bone loss by inhibiting the expansion of bone marrow adipose tissue (BMAT), restoring BMAT lipolysis and promoting bone formation. GSE regulated OVX-induced GM dysbiosis by reducing the abundance of opportunistic pathogenic bacteria, such as Alistipes, Turicibacter and Romboutsia, while elevating the abundance of beneficial bacteria, such as Bifidobacterium. The modified GM primarily impacted lipid and amino acid metabolism. Furthermore, the serum metabolites of GSE exhibited a significant enrichment in lipid metabolism. In summary, GSE shows potential as a functional food for preventing oestrogen deficiency-induced bone loss by modulating GM and metabolite-mediated lipid metabolism.

Estrogen deficiency induces changes in bone matrix bound water that do not closely correspond with bone turnover.

Postmenopausal osteoporosis, marked by estrogen deficiency, is a major contributor to osteoporotic fractures, yet early prediction of fractures in this population remains challenging. Our goal was to explore the temporal changes in bone-specific inflammation, oxidative stress, bone turnover, and bone-matrix water, and their relationship with estrogen deficiency-induced modifications in bone structure and mechanical properties. Additionally, we sought to determine if emerging clinically translatable imaging techniques could capture early bone modifications prior to standard clinical imaging. Two-month-old female Sprague Dawley rats (n = 48) underwent ovariectomy (OVX, n = 24) or sham operations (n = 24). A subgroup of n = 8 rats per group was sacrificed at 2-, 5-, and 10-weeks post-surgery to assess the temporal relationships of inflammation, oxidative stress, bone turnover, bone matrix water, mechanics, and imaging outcomes. OVX rats exhibited higher body weight compared to sham rats at all time points. By 5-weeks, OVX animals showed elevated markers of inflammation and oxidative stress in cortical bone, which persisted throughout the study, while cortical bone formation rate did not differ from sham until 10-weeks. DXA outcomes did not reveal differences between OVX and sham at any time point. Bound water, assessed using ultrashort echo time magnetic resonance imaging (UTE MRI), was lower in OVX at the earliest time point (2-weeks) and reduced again at 10-weeks with no difference at 5-weeks. These data demonstrate that bound water assessment using novel UTE MRI technology was lower at the earliest time point following OVX. However, no temporal relationship with bone turnover, inflammation, or oxidative stress was observed at the time points assessed in this study. These findings underscore both the increased need to understand bone hydration changes and highlight the usefulness of UTE MRI for non-invasive bone hydration measurements.

Giftedness and atypical sexual differentiation: enhanced perceptual functioning through estrogen deficiency instead of androgen excess.

Syndromic autism spectrum conditions (ASC), such as Klinefelter syndrome, also manifest hypogonadism. Compared to the popular Extreme Male Brain theory, the Enhanced Perceptual Functioning model explains the connection between ASC, savant traits, and giftedness more seamlessly, and their co-emergence with atypical sexual differentiation. Overexcitability of primary sensory inputs generates a relative enhancement of local to global processing of stimuli, hindering the abstraction of communication signals, in contrast to the extraordinary local information processing skills in some individuals. Weaker inhibitory function through gamma-aminobutyric acid type A (GABAA) receptors and the atypicality of synapse formation lead to this difference, and the formation of unique neural circuits that process external information. Additionally, deficiency in monitoring inner sensory information leads to alexithymia (inability to distinguish one's own emotions), which can be caused by hypoactivity of estrogen and oxytocin in the interoceptive neural circuits, comprising the anterior insular and cingulate gyri. These areas are also part of the Salience Network, which switches between the Central Executive Network for external tasks and the Default Mode Network for self-referential mind wandering. Exploring the possibility that estrogen deficiency since early development interrupts GABA shift, causing sensory processing atypicality, it helps to evaluate the co-occurrence of ASC with attention deficit hyperactivity disorder, dyslexia, and schizophrenia based on phenotypic and physiological bases. It also provides clues for understanding the common underpinnings of these neurodevelopmental disorders and gifted populations.

Unravelling the Crosstalk between Estrogen Deficiency and Gut-biotaDysbiosis in the Development of Diabetes Mellitus.

Estrogens are classically considered essential hormonal signals, but they exert profound effects in a number of physiological and pathological states, including glucose homeostasis and insulin resistance. Estrogen deficiency after menopause in most women leads to increased androgenicity and changes in body composition, and it is recommended to manipulate the ß-cell function of the pancreas, insulin-induced glucose transport, and hepatic glucose output, hence, the increasing incidence of type 2 diabetes mellitus. Recently, studies have reported that gut biota alteration due to estrogen deficiency contributes to altered energy metabolism and, hence, accentuates the pathology of diabetes mellitus. Emerging research suggests estrogen deficiency via genetic disposition or failure of ovaries to function in old age modulates the insulin resistance and glucose secretion workload on pancreatic beta cells by decreasing the levels of good bacteria such as Akkermansia muciniphila, Bifidobacterium spp., Lactobacillus spp., Faecalibacterium prausnitzii, Roseburia spp., and Prevotella spp., and increasing the levels of bad bacteria's such as Bacteroides spp., Clostridium difficile, Escherichia coli, and Enterococcus spp. Alteration in these bacteria's concentrations in the gut further leads to the development of impaired glucose uptake by the muscles, increased gluconeogenesis in the liver, and increased lipolysis and inflammation in the adipose tissues. Thus, the present review paper aims to clarify the intricate interactions between estrogen deficiency, gut microbiota regulation, and the development of diabetes mellitus.

G protein-coupled estrogen receptor 1 ameliorates nonalcoholic steatohepatitis through targeting AMPK-dependent signaling.

Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), has emerged as a prevalent cause of liver cirrhosis and hepatocellular carcinoma, posing severe public health challenges worldwide. The incidence of NASH is highly correlated with an increased prevalence of obesity, insulin resistance, diabetes, and other metabolic diseases. Currently, no approved drugs specifically targeted for the therapies of NASH partially due to the unclear pathophysiological mechanisms. G protein-coupled estrogen receptor 1 (GPER1) is a membrane estrogen receptor involved in the development of metabolic diseases such as obesity and diabetes. However, the function of GPER1 in NAFLD/NASH progression remains unknown. Here, we show that GPER1 exerts a beneficial role in insulin resistance, hepatic lipid accumulation, oxidative stress, or inflammation in vivo and in vitro. In particular, we observed that the lipid accumulation, inflammatory response, fibrosis, or insulin resistance in mouse NAFLD/NASH models were exacerbated by hepatocyte-specific GPER1 knockout but obviously mitigated by hepatic GPER1 activation in female and male mice. Mechanistically, hepatic GPER1 activates AMP-activated protein kinase signaling by inducing cyclic AMP release, thereby exerting its protective effect. These data suggest that GPER1 may be a promising therapeutic target for NASH.

Radiomic features of the hippocampal based on magnetic resonance imaging in the menopausal mouse model linked to neuronal damage and cognitive deficits.

Estrogen deficiency in the early postmenopausal phase is associated with an increased long-term risk of cognitive decline or dementia. Non-invasive characterization of the pathological features of the pathological hallmarks in the brain associated with postmenopausal women (PMW) could enhance patient management and the development of therapeutic strategies. Radiomics is a means to quantify the radiographic phenotype of a diseased tissue via the high-throughput extraction and mining of quantitative features from images acquired from modalities such as CT and magnetic resonance imaging (MRI). This study set out to explore the correlation between radiomics features based on MRI and pathological features of the hippocampus and cognitive function in the PMW mouse model. Ovariectomized (OVX) mice were used as PWM models. MRI scans were performed two months after surgery. The brain's hippocampal region was manually annotated, and the radiomic features were extracted with PyRadiomics. Chemiluminescence was used to evaluate the peripheral blood estrogen level of mice, and the Morris water maze test was used to evaluate the cognitive ability of mice. Nissl staining and immunofluorescence were used to quantify neuronal damage and COX1 expression in brain sections of mice. The OVX mice exhibited marked cognitive decline, brain neuronal damage, and increased expression of mitochondrial complex IV subunit COX1, which are pathological phenomena commonly observed in the brains of AD patients, and these phenotypes were significantly correlated with radiomics features (p < 0.05, |r|>0.5), including Original_firstorder_Interquartile Range, Original_glcm_Difference Average, Original_glcm_Difference Average and Wavelet-LHH_glszm_Small Area Emphasis. Meanwhile, the above radiomics features were significantly different between the sham-operated and OVX groups (p < 0.01) and were associated with decreased serum estrogen levels (p < 0.05, |r|>0.5). This initial study indicates that the above radiomics features may have a role in the assessment of the pathology of brain damage caused by estrogen deficiency using routinely acquired structural MR images.

Dihydrotanshinone I attenuates estrogen-deficiency bone loss through RANKL-stimulated NF-κB, ERK and NFATc1 signaling pathways.

Postmenopausal osteoporosis, a chronic condition that predominantly affects postmenopausal women, presents a significant impediment to their overall well-being. The condition arises from estrogen deficiency, leading to enhanced osteoclast activity. Salvia miltiorrhiza, a well-established Chinese herbal medicine with a history of clinical use for osteoporosis treatment, contains diverse active constituents that have shown inhibitory effects on osteoclast formation and bone loss. Dihydrotanshinone I (DTI), a phenanthrenonequinone compound derived from the root of Salvia miltiorrhiza, has been identified as a potential therapeutic agent, although its mechanism of action on osteoclasts remains elusive. In this study, we aimed to elucidate the inhibitory potential of DTI on RANKL-induced osteoclastogenesis. We observed the ability of DTI to effectively impede the expression of key osteoclast-specific genes and proteins, as assessed by Real-time PCR and Western Blotting analyses. Mechanistically, DTI exerted its inhibitory effects on osteoclast formation by modulating critical signaling pathways including NF-κB, ERK, and calcium ion signaling. Notably, DTI intervention disrupted the nuclear translocation and subsequent transcriptional activity of the NFATc1, thus providing mechanistic insights into its inhibitory role in osteoclastogenesis. To further assess the therapeutic potential of DTI, we employed an ovariectomized osteoporosis animal model to examine its impact on bone loss. Encouragingly, DTI demonstrated efficacy in mitigating bone loss induced by estrogen deficiency. In conclusion, our investigation elucidates the ability of DTI to regulate multiple signaling pathways activated by RANKL, leading to the inhibition of osteoclast formation and prevention of estrogen-deficiency osteoporosis. Consequently, DTI emerges as a promising candidate for the treatment of osteoporosis.

Estrogen deficiency accelerates postmenopausal atherosclerosis by inducing endothelial cell ferroptosis through inhibiting NRF2/GPX4 pathway.

Oxidative stress and lipid metabolism disorder caused by estrogen deficiency are regarded as the main causes of postmenopausal atherosclerosis, but the underlying mechanisms remain still unclear. In this study, ovariectomized (OVX) female ApoE-/- mice fed with high-fat diet were used to imitate postmenopausal atherosclerosis. The atherosclerosis progression was significantly accelerated in OVX mice, accompanied by the upregulation of ferroptosis indicators, including increased lipid peroxidation and iron deposition in the plaque and the plasma. While both estradiol (E2) and ferroptosis inhibitor ferrostatin-1 alleviated atherosclerosis in OVX mice, with the inhibition of lipid peroxidation and iron deposition, as well as the upregulation of xCT and GPX4, especially in endothelial cells. We further investigated the effects of E2 on ferroptosis in endothelial cells induced by oxidized-low-density lipoprotein or ferroptosis inducer Erastin. It was found that E2 exhibited anti-ferroptosis effect through antioxidative functions, including improving mitochondrial dysfunction and upregulating GPX4 expression. Mechanistically, NRF2 inhibition attenuated the effect of E2 against ferroptosis as well as the upregulation of GPX4. Our findings revealed that endothelial cell ferroptosis played a pivotal role in postmenopausal atherosclerosis progression, and the NRF2/GPX4 pathway activation contributed to the protection of E2 against endothelial cell ferroptosis.

Safranal inhibits estrogen-deficiency osteoporosis by targeting Sirt1 to interfere with NF-κB acetylation.

BACKGROUND: Osteoporosis is a prevalent bone metabolic disease in menopause, and long-term medication is accompanied by serious side effects. Estrogen deficiency-mediated hyperactivated osteoclasts is the initiating factor for bone loss, which is regulated by nuclear factor-κB (NF-κB) signaling. Safranal (Saf) is a monoterpene aldehyde produced from Saffron (Crocus sativus L.) and possesses multiple biological properties, particularly the anti-inflammatory property. However, Saf's role in osteoporosis remains unknown. PURPOSE: This study aims to validate the role of Saf in osteoporosis and explore the potential mechanism. STUDY DESIGN: The RANKL-exposed mouse BMM (bone marrow monocytes) and the castration-mediated osteoporosis model were applied to explore the effect and mechanism of Saf in vitro and in vivo. METHOD: The effect of Saf on osteoclast formation and function were assessed by TRAcP staining, bone-resorptive experiment, qPCR, immunoblotting and immunofluorescence, etc. Micro-CT, HE, TRAcP and immunohistochemical staining were performed to estimate the effects of Saf administration on OVX-mediated osteoporosis in mice at imaging and histological levels. RESULTS: Saf concentration-dependently inhibited RANKL-mediated osteoclast differentiation without affecting cellular viability. Meanwhile, Saf-mediated anti-osteolytic capacity and Sirt1 upregulation were also found in ovariectomized mice. Mechanistically, Saf interfered with NF-κB signaling by activating Sirt1 to increase p65 deacetylation and inactivating IKK to decrease IκBα degradation. CONCLUSION: Our results support the potential application of Saf as a therapeutic agent for osteoporosis.

Pulsed electromagnetic field attenuates bone fragility in estrogen-deficient osteoporosis in rats.

BACKGROUND: The pulsed electromagnetic fields (PEMFs) seem effective in increasing bone mineral density and promoting osteogenesis and bone healing. OBJECTIVE: To examine the effect of two different modalities of PEMFs therapy in comparison with the recommended pharmacological treatment on experimental osteoporosis in rats. METHODS: The experimental model of estrogen-deficient osteoporosis induced by ovariectomy was used in this study. The animals were exposed to PEMFs of various frequencies (40 Hz and 25 Hzk), intensities (10 mT and 36.4 µT), lengths of exposure, and the effects were compared with the standard treatment with pamidronate, vitamin D, and calcium supplementation. RESULTS: The application of PEMF40Hz, significantly reduced the osteoporotic bone loss in female rats that were confirmed with biochemical, biomechanical, and histological analyses. These effects were more pronounced than in osteoporotic animals treated with pamidronate, vitamin D, and calcium supplementation. On the contrary, the exposure to PEMF25Hz did not show restorative effects but led to further progression of osteoporosis. CONCLUSION: The exposure to PEMF40Hz, significantly restored osteoporosis and attenuated bone fragility in comparison to the rats exposed to PEMF25Hz or those treated with pamidronate, vitamin D, and calcium supplementation.

Voluntary wheel running alters markers of amyloid-beta precursor protein processing in an ovarian hormone depleted model.

Introduction: Aberrant cleavage of the transmembrane protein, amyloid-beta precursor protein (ABPP), results in the overproduction of amyloid-beta (AB) peptides which can form senile plaques in the brain. These plaques can get lodged within synapses and disrupt neuronal communication ultimately leading to rampant neuron death. The rate-limiting enzyme in AB production is beta-site ABPP cleaving enzyme 1 (BACE1). In females, estrogen loss is associated with increases in AB and BACE1 content and activity. Exercise is known to have anti-amyloidogenic effects and may be able to alter BACE1 in cases of ovarian hormone depletion. This study aimed to examine the effects of physical activity on BACE1 in intact and ovariectomized female mice. Methods: Female C57BL/6 mice (24 weeks old) underwent bilateral ovariectomy (OVX; n=20) or SHAM surgery (SHAM; n=20). Mice were assigned to one of four groups (n=10/group) for 8 weeks: (1) sham (SHAM), (2) sham with a wheel (SHAM VWR), (3) ovariectomized (OVX), or (4) ovariectomized with a wheel (OVX VWR). Results: Novel object recognition testing demonstrated that OVX mice had a lower percentage of novel object investigation time compared to SHAM. OVX mice also had higher prefrontal cortex BACE1 activity compared to SHAM (p<0.0001), while the OVX+VWR activity was not different from SHAM. Discussions: Our results demonstrate that voluntary wheel running in an ovariectomized model prevented increases in BACE1 activity, maintained memory recall, and may provide a method of slowing the progression of Alzheimer's disease.

Effects of the Pulsed Electromagnetic Fields on Experimental Periodontitis and Estrogen Deficiency.

Periodontitis is an inflammatory disease resulting from a complex polymicrobial infection that causes tissue destruction in susceptible individuals. Osteoporosis has been associated with greater clinical attachment loss in patients with periodontitis. Experimental studies have shown positive results in the treatment of osteoporosis through pulsed electromagnetic field (PEMF) stimulation. The aim of this study was to evaluate the effects of PEMF in the presence of estrogen deficiency associated with periodontitis, verifying its role in bone metabolism and in the inflammatory response. Sixty rats were divided into four groups: Sham surgery + ligature-induced periodontitis (P); Sham surgery + ligature-induced periodontitis + PEMF therapy (P + PEMF); Ovariectomy surgery + ligature-induced periodontitis (P + OVX); Ovariectomy surgery + ligature-induced periodontitis + PEMF therapy (P + OVX + PEMF). The area of bone loss in the furcation region (BL), connective tissue attachment loss (CTAL) and alveolar bone loss (ABL), BV/TV and BMD were evaluated. In addition to immunohistochemical labelling of RANKL, OPG, and TRAP and the inflammatory response of interleukin (IL)-1b, IL-6, TNF-α, IL-10, and vascular endothelial growth factor. P + OVX showed significant BL in relation to P + PEMF and the greatest CTAL and ABL. P + OVX and P + OVX + PEMF showed a significant reduction in BV/TV (%). P and P + PEMF showed a significantly lesser amount of Tb.Sp (mm) while P + OVX and P + OVX + PEMF showed a lesser of Tb.N. P + PEMF had the greatest BMD. P + OVX presented higher RANKL and lower OPG immunolabeling than other groups. P + PEMF and P + OVX + PEMF showed a reduction on all biomarkers evaluated. The application of PEMF seems to attenuate the effects of bone loss in the presence of periodontitis and ovariectomy. © 2022 Bioelectromagnetics Society.

Women With Turner Syndrome Are Both Estrogen and Androgen Deficient: The Impact of Hormone Replacement Therapy.

CONTEXT: Women with Turner syndrome (TS) suffer from hypergonadotropic hypogonadism, causing a deficit in gonadal hormone secretion. As a consequence, these women are treated with estrogen from the age of 12 years, and later in combination with progesterone. However, androgens have been given less attention. OBJECTIVE: To assess sex hormone levels in women with TS, both those treated and those nontreated with hormone replacement therapy (HRT), and investigate the impact of HRT on sex hormone levels. METHODS: At Aarhus University Hospital, 99 women with TS were followed 3 times from August 2003 to February 2010. Seventeen were lost during follow-up. Control group 1 consisted of 68 healthy age-matched control women seen once during this period. Control group 2 consisted of 28 young, eumenorrheic women sampled 9 times throughout the same menstrual cycle. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17ß-estradiol, estrone sulfate, DHEAS, testosterone, free androgen index, androstenedione, 17-OH progesterone, and sex hormone-binding globulin (SHBG) were analyzed. RESULTS: All androgens, 17-OH progesterone, and sex hormone-binding globulin (SHBG) were 30% to 50% lower in TS compared with controls (P < 0.01). FSH, LH, and estrone sulfate were more than doubled in women with TS compared with controls (P < 0.02). Using principal component analysis, we describe a positive correlation between women with TS receiving HRT, elevated levels of SHBG, and decreased levels of androgens. CONCLUSION: The sex hormone profile in TS reveals a picture of androgen deficiency, aggravated further by HRT. Conventional HRT does not normalize estradiol levels in TS.

Osteoporosis Due to Hormone Imbalance: An Overview of the Effects of Estrogen Deficiency and Glucocorticoid Overuse on Bone Turnover.

Osteoporosis is a serious health issue among aging postmenopausal women. The majority of postmenopausal women with osteoporosis have bone loss related to estrogen deficiency. The rapid bone loss results from an increase in bone turnover with an imbalance between bone resorption and bone formation. Osteoporosis can also result from excessive glucocorticoid usage, which induces bone demineralization with significant changes of spatial heterogeneities of bone at microscale, indicating potential risk of fracture. This review is a summary of current literature about the molecular mechanisms of actions, the risk factors, and treatment of estrogen deficiency related osteoporosis (EDOP) and glucocorticoid induced osteoporosis (GIOP). Estrogen binds with estrogen receptor to promote the expression of osteoprotegerin (OPG), and to suppress the action of nuclear factor-κß ligand (RANKL), thus inhibiting osteoclast formation and bone resorptive activity. It can also activate Wnt/ß-catenin signaling to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts, rather than adipocytes. The lack of estrogen will alter the expression of estrogen target genes, increasing the secretion of IL-1, IL-6, and tumor necrosis factor (TNF). On the other hand, excessive glucocorticoids interfere the canonical BMP pathway and inhibit Wnt protein production, causing mesenchymal progenitor cells to differentiate toward adipocytes rather than osteoblasts. It can also increase RANKL/OPG ratio to promote bone resorption by enhancing the maturation and activation of osteoclast. Moreover, excess glucocorticoids are associated with osteoblast and osteocyte apoptosis, resulting in declined bone formation. The main focuses of treatment for EDOP and GIOP are somewhat different. Avoiding excessive glucocorticoid use is mandatory in patients with GIOP. In contrast, appropriate estrogen supplement is deemed the primary treatment for females with EDOP of various causes. Other pharmacological treatments include bisphosphonate, teriparatide, and RANKL inhibitors. Nevertheless, more detailed actions of EDOP and GIOP along with the safety and effectiveness of medications for treating osteoporosis warrant further investigation.

Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency.

The incidence of nonalcoholic fatty liver disease (NAFLD) in postmenopausal women has increased significantly. Estrogen plays a very important role in NAFLD, but whether NAFLD in premenopausal women was caused by estrogen deficiency was unknown. Thus, it is of great clinical significance to explore the mechanism of NAFLD in premenopausal women. Gut microbiota and its metabolites short chain fatty acids (SCFA) have been shown to play important roles in the development of NAFLD. In this study, we investigated the impact of gut microbiota and SCFA in NAFLD patients and mice caused by estrogen deficiency. We showed that premenopause NAFLD patients had much lower estrogen levels. Estrogen deficient mice, due to ovariectomy (OVX), suffered more severe liver steatosis with an elevated body weight, abdominal fat weight, serum triglycerides and deterioration in hepatic steatosis. Altered gut microbiota composition and decreased butyrate content were found in NAFLD patients and in OVX mice. Furthermore, fecal microbiota transplantation (FMT) or supplementing with butyrate alleviated NAFLD in OVX mice. The production of antimicrobial peptides (AMP) Reg3É£, ß-defensins and the expression of intestinal epithelial tight junction, including ZO-1 and Occluding-5, were decreased in the OVX mice compared to control mice. Upregulation of PPAR-É£ and VLDLR, downregulation of PPAR-ɑ indicated that OVX mice suffered from abnormal lipid metabolism. These data indicate that changes in the gut microbiota and SCFA caused by estrogen reduction, together with a disorder in AMP production and lipid metabolism, promote NAFLD, thus provide SCFAs derived from microbiota as new therapeutic targets for the clinical prevention and treatment of NAFLD.

Combination of molecular docking and liver transcription sequencing analysis for the evaluation of salt-processed psoraleae fructus-induced hepatotoxicity in ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Salt-processed Psoraleae fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, SPF-associated hepatotoxicity is a known health hazard. Cholestasis is often associated with SPF-induced hepatotoxicity. Notably, clinical liver injury is a common side effect of SPF in the treatment of osteoporosis; however, the exact mechanism underlying this phenomenon is unclear. AIM OF THE STUDY: To evaluate SPF-induced hepatotoxicity in an ovariectomized murine model of estrogen deficiency and examine the mechanisms underlying this process. MATERIALS AND METHODS: To explore the molecular mechanism of SPF-induced cholestatic liver injury, different concentrations of SPF (5 and 10 g/kg) were intragastrically administered to ovariectomized and non-ovariectomized female ICR mice for 30 days. RESULTS: SPF-treated mice showed noticeably swollen hepatocytes, dilated bile ducts, and elevated levels of serum biochemical markers. Compared to ovariectomized mice, these changes were more prominent in non-ovariectomized mice. According to the sequence data, a total of 6689 mRNAs were identified. Compared with the control group, 1814 differentially expressed mRNAs were identified in the group treated with high SPF doses (SPHD), including 939 upregulated and 875 downregulated mRNAs. Molecular docking and Western blot experiments showed that liver injury was closely related to the estrogen levels. Compared with the negative control group, the expression levels of FXR, Mrp2, CYP7a1, BSEP, SULT1E1, HNF4a, and Nrf2 decreased in the estradiol-treated (E2), low-dose SPF-treated (SPLD), and SPHD groups. Interestingly, the expression levels of FXR, CYP7a1, SULT1E1, and HNF4α were significantly higher in the ovariectomized groups than in the non-ovariectomized groups (#P < 0.05; ###P < 0.001). CONCLUSIONS: Overall, this study demonstrates that SPF downregulates key enzymes involved in cholesterol and bile acid biosyntheses, posing a risk for cholestatic liver injury. SPF also regulates the FXR-SULT1E signaling pathway via HNF4α, which is an important causative factor of cholestasis. Moreover, the severity of liver damage was significantly lower in the ovariectomized groups than in the non-ovariectomized group. These results suggest that the estrogen level is the most critical factor determining liver injury.

Unique Transcriptomic Changes Underlie Hormonal Interactions During Mammary Histomorphogenesis in Female Pigs.

Successful lactation and the risk for developing breast cancer depend on growth and differentiation of the mammary gland (MG) epithelium that is regulated by ovarian steroids (17ß-estradiol [E] and progesterone [P]) and pituitary-derived prolactin (PRL). Given that the MG of pigs share histomorphogenic features present in the normal human breast, we sought to define the transcriptional responses within the MG of pigs following exposure to all combinations of these hormones. Hormone-ablated female pigs were administered combinations of E, medroxyprogesterone 17-acetate (source of P), and either haloperidol (to induce PRL) or 2-bromo-α-ergocryptine. We subsequently monitored phenotypic changes in the MG including mitosis, receptors for E and P (ESR1 and PGR), level of phosphorylated STAT5 (pSTAT5), and the frequency of terminal ductal lobular unit (TDLU) subtypes; these changes were then associated with all transcriptomic changes. Estrogen altered the expression of approximately 20% of all genes that were mostly associated with mitosis, whereas PRL stimulated elements of fatty acid metabolism and an inflammatory response. Several outcomes, including increased pSTAT5, highlighted the ability of E to enhance PRL action. Regression of transcriptomic changes against several MG phenotypes revealed 1669 genes correlated with proliferation, among which 29 were E inducible. Additional gene expression signatures were associated with TDLU formation and the frequency of ESR1 or PGR. These data provide a link between the hormone-regulated genome and phenome of the MG in a species having a complex histoarchitecture like that in the human breast, and highlight an underexplored synergy between the actions of E and PRL during MG development.

Cannabidiol reverses memory impairments and activates components of the Akt/GSK3ß pathway in an experimental model of estrogen depletion.

Clinical and preclinical evidence has indicated that estrogen depletion leads to memory impairments and increases the susceptibility to neural damage. Here, we have sought to investigate the effects of Cannabidiol (CBD) a non-psychotomimetic compound from Cannabis sativa, on memory deficits induced by estrogen depletion in rats, and its underlying mechanisms. Adult rats were subjected to bilateral ovariectomy, an established estrogen depletion model in rodents, or sham surgery and allowed to recover for three weeks. After that, they received daily injections of CBD (10 mg/kg) for fourteen days. Rats were tested in the inhibitory avoidance task, a type of emotionally-motivated memory. After behavioral testing they were euthanized, and their hippocampi were isolated for analysis of components of the Akt/GSK3ß survival pathway and the antiapoptotic protein Bcl2. Results revealed that ovariectomy impaired avoidance memory, and CBD was able to completely reverse estrogen depletion-induced memory impairment. Ovariectomy also reduced Akt/GSK3ß pathway's activation by decreasing the phosphorylation levels of Akt and GSK3ß and Bcl2 levels, which were ameliorated by CBD. The present results indicate that CBD leads to a functional recovery accompanied by the Akt/GSK3ß survival pathway's activation, supporting its potential as a treatment for estrogen decline-induced deterioration of neural functioning and maintenance.