OBJECTIVE: To observe the regulatory effects of moxibustion at "Guanyuan" (CV4) on the synthesis of extragonadal estradiol (E₂) and the expression of estrogen receptor (ER) in ovariectomized rats, aiming to explore the mechanism of moxibustion treatment for perimenopausal syndrome. METHODS: Forty-eight SD female rats of SPF grade were randomly divided into a sham-operation group, a model group and a moxibustion group, with 16 rats in each group. The model group and the moxibustion group underwent bilateral ovariectomy by the back incision method. Ten days after surgery, moxibustion was applied at "Guanyuan" (CV4) in the moxibustion group, 30 min each time, once a day for 10 days. After intervention, in the 3 groups, the body mass and uterus weight were measured; the serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and E₂, as well as the skin and hypothalamus levels of E₂ were detected by ELISA; the mRNA expression of aromatase (P450arom) in the skin and hypothalamus was detected by real-time PCR; the expression of ERα and ERβ in the hypothalamus, skin, and uterus was observed by immunofluorescence staining, and the density of positive cells was calculated using the Aipathwell digital pathology image analysis software. RESULTS: Compared with the sham-operation group, the body mass was increased (P<0.01) and the uterus weight was decreased (P<0.001) in the model group. Compared with the model group, the body mass was decreased in the moxibustion group (P<0.01). Compared with the sham-operation group, in the model group, the serum, hypothalamus and skin levels of E₂ were decreased (P<0.01, P<0.05), while the serum levels of FSH and LH were increased (P<0.01); the expression of ERα and ERβ in the skin, hypothalamus and uterus was decreased (P<0.05, P<0.001). Compared with the model group, in the moxibustion group, the serum levels of E₂ and LH, as well as the hypothalamus and skin levels of E₂ were increased (P<0.05, P<0.01); the mRNA expression of P450arom, as well as the expression of ERα and ERβ in the skin and hypothalamus were increased (P<0.05). CONCLUSION Moxibustion at "Guanyuan" (CV4) reduces the body mass of ovariectomized rats by enhancing the synthesis of extragonadal E₂ and increasing the expression of ER in the skin and hypothalamus, yet it does not alleviate uterine atrophy.
Animals ; Female ; Moxibustion ; Rats ; Ovariectomy ; Acupuncture Points ; Rats, Sprague-Dawley ; Humans ; Receptors, Estrogen/genetics* ; Estrogens/metabolism* ; Estradiol/metabolism* ; Hypothalamus/metabolism* ; Follicle Stimulating Hormone/blood* ; Aromatase/genetics* ; Luteinizing Hormone/blood* ; Skin/metabolism*

OBJECTIVE: To investigate the effect of human adipose-derived mesenchymal stem cells (hASCs) exosomes on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) extracted from osteoporotic mice, and to evaluate the effect of hASCs exosomes on preventing bone loss induced by estrogen deficiency. METHODS: hASCs exosomes were extracted by ultracentrifugation. The osteoporotic mice were established by bilateral ovariectomy (OVX). BMSCs were isolated from osteo-porotic mice and cultured for further analysis. In the experimental group, these BMSCs were exposed to an osteogenic induction medium supplemented with hASCs exosomes to evaluate their potential effects on osteogenesis. In contrast, the control group was treated with the same osteogenic induction medium, but without the addition of hASCs exosomes, to serve as a baseline comparison for the study. To comprehensively assess the osteogenic differentiation of BMSCs influenced by hASCs exosomes, alkaline phosphatase (ALP) staining, ALP activity quantitative analysis and quantitative reverse transcription polymerase chain reaction (qPCR) were performed. These evaluations provided critical insights into the role of hASCs exosomes in promoting osteoblast differentiation and bone formation in osteoporotic conditions. The fluorescence labeled hASCs exosomes were injected via the tail vein to observe the biodistribution of exosomes. Two weeks after OVX, the mice were divided into three groups: The experimental group consisted of estrogen-deficient mice receiving hASCs exosome injections; the negative control group consisted of estrogen-deficient mice receiving phosphate-buffered saline (PBS) injections; and the positive control group consisted of mice that underwent Sham surgery and received PBS injections.The injections were administered once every 3 days, for a total of 8 injections. Afterward, the femurs were collected from the mice, and micro-computed tomography (micro-CT) was performed to measure bone mineral density and conduct bone morphometric analysis. RESULTS: hASCs exosomes were successfully extracted using ultracentrifugation. After the induction by hASCs exosomes, ALP staining and ALP activity in the BMSCs extracted from osteoporotic mice were significantly enhanced, the expression of osteogenesis related genes in BMSCs were significantly up-regulated. More trabecular bone and higher bone mineral density were observed in estrogen-deficient mice injected with hASCs exosomes compared with estrogen-deficient mice injected with PBS, and there was no significant decrease in bone mineral density compared with the Sham operation group. CONCLUSION hASCs exosomes promoted the osteogenic differentiation of BMSCs extracted from osteoporotic mice. hASCs exosomes prevented bone loss induced by estrogen deficiency.
Animals ; Mesenchymal Stem Cells/cytology* ; Exosomes ; Estrogens/deficiency* ; Humans ; Osteogenesis ; Cell Differentiation ; Female ; Mice ; Osteoporosis/prevention & control* ; Ovariectomy ; Adipose Tissue/cytology* ; Cells, Cultured

Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.
Female ; Mice ; Demethylation/drug effects* ; Embryonic Stem Cells ; Estrogens/administration & dosage* ; Gene Expression/drug effects* ; Histones/metabolism* ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Mice, Inbred C57BL ; Oocytes ; Ovary/drug effects* ; Reproductive Techniques, Assisted ; Animals

Perimenopausal period is a period with high incidence of female depression, which shows the symptoms of depressed mood and disturbed mind. The pathogenesis of the disease is not clear and it is urgent to search for efficient treatment. Leptin is a hormone secreted by fat cells and plays a role in both metabolism and neuroprotection. In recent years, leptin has been reported to ameliorate perimenopausal depression, and leptin is closely related to estrogen synthesis and secretion. Therefore, leptin may be used as a potential molecular target for the treatment of perimenopausal depression. In this paper, the research on the relationship between leptin and perimenopausal depression is reviewed.
Depression ; Leptin ; Estrogens

Cerebral venous sinus thrombosis ( CVST) results from occlusion of cerebral venous sinuses, usually resulting in hemorrhagic infarction. It is a rare type of stroke affecting 3-5 per million people, often due to hypercoagulable states from clotting factor abnormalities or diseases like cancers, autoimmune and collagen vascular disease. Headache, visual changes, changes in sensorium, focal neurologic signs, seizures, and coma are some of the symptoms.

The role of exogenous estrogen in developing CVST among transgenders has not been reported frequently in literature. We report a 26-year-old transgender female who presented with throbbing headache after four years of exogenous high dose parenteral and oral estrogen. Magnetic resonance venography findings showed dural sinus thrombosis involving the left internal jugular vein, left sigmoid sinus, left transverse sinus, straight sinus, torcula and posterior aspect of the superior sagittal sinus. Patient was treated with topiramate, steroids and anticoagulants. Patient symptoms improved and was subsequently sent with home medications edoxaban. This case underscores the importance of monitoring the use of hormonal therapy in transgender individuals.

This report is an example of a rare cause of thrombosis secondary to self-administration of parenteral and oral estrogen. Prompt diagnosis in this patient resulted in the prevention of a catastrophic event like a major stroke, highlighting the importance of vigilance in managing hormone therapy. Increasing awareness about transgender issues can improve health and reduce inequities in this population. Cerebral venous sinus thrombosis ( CVST) results from occlusion of cerebral venous sinuses, usually resulting in hemorrhagic infarction. It is a rare type of stroke affecting 3-5 per million people, often due to hypercoagulable states from clotting factor abnormalities or diseases like cancers, autoimmune and collagen vascular disease. Headache, visual changes, changes in sensorium, focal neurologic signs, seizures, and coma are some of the symptoms.

The role of exogenous estrogen in developing CVST among transgenders has not been reported frequently in literature. We report a 26-year-old transgender female who presented with headache after 4 years of exogenous high dose parenteral and oral estrogen. Magnetic resonance venography findings showed dural sinus thrombosis involving the left internal jugular vein, left sigmoid sinus, left transverse sinus, straight sinus, torcula and posterior aspect of the superior sagittal sinus. Patient was treated with topiramate, steroids and anticoagulants. Patient symptoms improved and was subsequently sent home on edoxaban. This case underscores the importance of monitoring hormonal therapy in transgender individuals.

This report is an example of a rare cause of thrombosis secondary to self-administration of parenteral and oral estrogen. Prompt diagnosis in this patient resulted in the prevention of a catastrophic event like a major stroke, highlighting the importance of vigilance in managing hormone therapy. Increasing awareness about transgender issues can improve health and reduce inequities in this population.

Schizophrenia is a chronic psychiatric disorder with complex etiology and diverse clinical manifestations, whose pathogenesis and triggering factors remain incompletely understood. Numerous studies have demonstrated significant gender differences in the age of onset, clinical presentation, disease progression, treatment efficacy, and prognosis among patients with schizophrenia. These differences are largely attributed to variations in sex hormone levels, with estrogen emerging as a key focus of research. Some studies suggest that adjunctive estrogen therapy during schizophrenia treatment not only alleviates symptoms but also reduces the required dosage of antipsychotic medications. A systematic review of research on estrogen as an adjunctive treatment for schizophrenia may provide new perspectives and references for future therapeutic strategies.
Humans ; Schizophrenia/drug therapy* ; Estrogens/therapeutic use* ; Antipsychotic Agents/administration & dosage* ; Male ; Female ; Sex Characteristics ; Clinical Trials as Topic ; Estrogen Replacement Therapy

Embryo implantation involves a complex interaction between the embryo and the endometrium of the mother, the study of which faces a variety of problems. The modeling of endometrial epithelial organoids and endometrial assembloids provides a new way to study the process of embryo implantation in vitro. This paper summarized the latest research progress in embryo implantation, the regulation mechanism of endometrial receptivity by estrogen- progesterone coordination and embryo-derived signals, the establishment of endometrial organoids, and the development and application of endometrial assembloids in the research on mother-embryo interaction, providing new strategies for studying the communication between embryo and maternal uterus during implantation.
Endometrium/physiology* ; Organoids/cytology* ; Embryo Implantation/physiology* ; Female ; Animals ; Progesterone/pharmacology* ; Pregnancy ; Estrogens/metabolism* ; Humans

Endometrial cancer is the most common gynecological malignancy, affecting up to 3% of women at some point during their lifetime (Morice et al., 2016; Li and Wang, 2021). Based on the pathogenesis and biological behavioral characteristics, endometrial cancer can be divided into estrogen-dependent (I) and non-estrogen-dependent (II) types (Ulrich, 2011). Type I accounts for approximately 80% of cases, of which the majority are endometrioid carcinomas, and the remaining are mucinous adenocarcinomas (Setiawan et al., 2013). It is generally recognized that long-term stimulation by high estrogen levels with the lack of progesterone antagonism is the most important risk factor; meanwhile, there is no definite conclusion on the specific pathogenesis. The incidence of endometrial cancer has been on the rise during the past two decades (Constantine et al., 2019; Gao et al., 2022; Luo et al., 2022). Moreover, the development of assisted reproductive technology and antiprogestin therapy following breast cancer surgery has elevated the risk of developing type I endometrial cancer to a certain extent (Vassard et al., 2019). Therefore, investigating the influence of estrogen in type I endometrial cancer may provide novel concepts for risk assessment and adjuvant therapy, and at the same time, provide a basis for research on new drugs to treat endometrial cancer.
Female ; Humans ; Proto-Oncogene Proteins c-akt ; Phosphatidylinositol 3-Kinases ; Endometrial Neoplasms ; Estrogens ; Breast Neoplasms ; DNA Helicases

Estrogen impacts neural development; meanwhile, it has a protective effect on the brain. Bisphenols, primarily bisphenol A (BPA), can exert estrogen-like or estrogen-interfering effects by binding with estrogen receptors. Extensive studies have suggested that neurobehavioral problems, such as anxiety and depression, can be caused by exposure to BPA during neural development. Increasing attention has been paid to the effects on learning and memory of BPA exposure at different developmental stages and in adulthood. Further research is required to elucidate whether BPA increases the risk of neurodegenerative diseases and the underlying mechanisms, as well as to assess whether BPA analogs, such as bisphenol S and bisphenol F, influence the nervous system.
Receptors, Estrogen/metabolism* ; Estrogens ; Benzhydryl Compounds/pharmacology* ; Nervous System/metabolism*

Endometriosis, a heterogeneous, inflammatory, and estrogen-dependent gynecological disease defined by the presence and growth of endometrial tissues outside the lining of the uterus, affects approximately 5-10% of reproductive-age women, causing chronic pelvic pain and reduced fertility. Although the etiology of endometriosis is still elusive, emerging evidence supports the idea that immune dysregulation can promote the survival and growth of retrograde endometrial debris. Peritoneal macrophages and natural killer (NK) cells exhibit deficient cytotoxicity in the endometriotic microenvironment, leading to inefficient eradication of refluxed endometrial fragments. In addition, the imbalance of T-cell subtypes results in aberrant cytokine production and chronic inflammation, which contribute to endometriosis development. Although it remains uncertain whether immune dysregulation represents an initial cause or merely a secondary enhancer of endometriosis, therapies targeting altered immune pathways exhibit satisfactory effects in preventing disease onset and progression. Here, we summarize the phenotypic and functional alterations of immune cells in the endometriotic microenvironment, focusing on their interactions with microbiota and endocrine and nervous systems, and how these interactions contribute to the etiology and symptomology of endometriosis.
Female ; Humans ; Endometriosis/metabolism* ; Killer Cells, Natural/metabolism* ; T-Lymphocytes/metabolism* ; Estrogens ; Endometrium/metabolism*