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

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

OBJECTIVES: Inflammation is a major mechanism underlying coronary heart disease (CHD) and C-reactive protein (CRP) is a marker of inflammation. When administered soon after menopause, menopausal hormone therapy (MHT) prevents CHD. This study was conducted to examine the impact of estrogen by administration route on CRP in postmenopausal Korean women using micronized progesterone (MP4) for endometrial protection. METHODS: This retrospective cohort study included 129 healthy women without CHD risk factors. Eighty-nine women took oral estrogen (conjugated equine estrogen, 0.625 mg/day or equivalent), and 40 women applied a 1.5-mg/day 0.1% percutaneous estradiol gel. MP4 was added in 82 women with an intact uterus. The CRP level was measured at baseline and three and six months after initiation of MHT. RESULTS: The baseline characteristics were comparable between the MHT groups except current age and age at menopause. After controlling for age, menopausal age, body mass index, and basal CRP, no significant change in CRP was observed in the oral estrogen group (n = 29). Follow-up CRP levels were also similar to the baseline in the percutaneous estrogen group (n = 18). However, three-month CRP was significantly lower than six-month CRP, and there was a significant time trend within the percutaneous estrogen group. However, the group difference did not reach statistical significance. CRP also did not differ by addition of MP4 in either group. CONCLUSIONS: In postmenopausal Korean women, no change in CRP was observed with oral estrogen, while percutaneous estrogen might decrease CRP. The estrogenic impacts were not influenced by adding MP4.
Body Mass Index ; C-Reactive Protein ; Cohort Studies ; Coronary Disease ; Drug Administration Routes ; Estradiol ; Estrogens ; Female ; Follow-Up Studies ; Hormone Replacement Therapy ; Humans ; Inflammation ; Menopause ; Postmenopause ; Progesterone ; Retrospective Studies ; Risk Factors ; Uterus

Ospemifene—a third-generation selective estrogen receptor modulator approved by the Food and Drug Administration in 2013—is an oral medication for the treatment of dyspareunia. In postmenopausal women with vulvovaginal atrophy, ospemifene significantly improves the structure and pH levels of the vagina, reducing dyspareunia. It is available as a 60-mg tablet; hence, women who may have had prior difficulty with vaginal administration or on-demand use of nonprescription lubricants and moisturizers would likely prefer this form of treatment. Preclinical studies demonstrated that ospemifene has an estrogen agonist action on the bone, reducing the cell proliferation of ductal carcinoma in an in situ model. Studies evaluating the safety of treatment for up to 52 weeks have shown that ospemifene is a safe medication with minimal impact on the endometrium. Further studies with larger number of subjects are necessary to better conclude its effects and long-term safety.
Administration, Intravaginal ; Atrophy* ; Carcinoma, Ductal ; Cell Proliferation ; Dyspareunia ; Endometrium ; Estrogens ; Female ; Humans ; Hydrogen-Ion Concentration ; Lubricants ; Menopause ; Selective Estrogen Receptor Modulators ; Tamoxifen ; United States Food and Drug Administration ; Vagina ; Vulva

Post-menopausal osteoporosis (PMO) is a major global human health concern. Owing to the need for therapeutic drugs without side effects, natural extracts containing various polyphenolic compounds that may exert estrogenic effects have been studied in depth. Rhus verniciflua Stokes (RVS), which has been used as a traditional herbal medicine for centuries in Korea, was recently revealed to exert estrogenic effects attributable to its bioactive ingredients sulfuretin and butein, which have strong estrogen receptor–binding affinities. In this study, the protective potential of RVS in PMO was evaluated by using an experimental animal model of PMO, which was established by ovariectomy (OVX) of female Sprague Dawley rats. The oral administration of RVS at 20 mg/kg or 100 mg/kg for 8 weeks markedly protected against OVX-induced atrophy of the uterine tube and reversed the elevation in the ratio of serum receptor activator of nuclear factor-κB ligand to osteoprotegerin, which is a marker of disease severity. In addition, RVS inhibited OVX-induced tibia bone loss, activated osteogenic activity, and suppressed osteoclastic activity in the tibial epiphyseal plate, a region of bone remodeling. Collectively, these factors indicated that the oral intake of RVS might be beneficial for the prevention of PMO.
Administration, Oral ; Atrophy ; Bone Remodeling ; Estrogens ; Fallopian Tubes ; Female ; Growth Plate ; Herbal Medicine ; Humans ; Korea ; Models, Animal ; Models, Theoretical* ; Osteoclasts ; Osteoporosis, Postmenopausal* ; Osteoprotegerin ; Ovariectomy ; Rats, Sprague-Dawley ; Rhus* ; Tibia

BACKGROUNDMenopausal hormone therapy (MHT) has been proven to have beneficial effects on several components of metabolic syndrome. However, the effects vary according to different regimens, dosages, and duration of MHT. The aim of the study was to evaluate the effect of standard-dose 0.625 mg conjugated equine estrogen (CEE) and half-dose 0.3 mg CEE daily with different progestogens in a continuous sequential regimen on postmenopausal metabolic parameters in generally healthy postmenopausal women.

METHODSA prospective, open-label, randomized controlled clinical trial was conducted between February 2014 and December 2015. Totally 123 Chinese postmenopausal women with climacteric symptoms were included in this study and were randomly assigned to three groups: Group A received CEE 0.3 mg/micronized progesterone (MP) 100 mg daily; Group B received CEE 0.625 mg/MP 100 mg daily; and Group C received CEE 0.625 mg/dydrogesterone 10 mg daily. Drugs were given in a continuous sequential pattern. The duration of treatment was 12 months. Clinical, anthropometrical, and metabolic variables were measured. Data were analyzed according to intention-to-treat analysis, using Student's t-test and analysis of variance.

RESULTSA total of 107 participants completed the 12-month follow-up and were included in the data analysis. At 12 months of treatment, high-density lipoprotein cholesterol and apolipoprotein A significantly increased, and low-density lipoprotein cholesterol, fasting glucose, and glycosylated hemoglobin significantly decreased in Groups B and C, compared with baseline (all P < 0.05). Among the three groups, only Group C showed significantly increased triglycerides compared with baseline (1.61 ± 0.80 mmol/L vs. 1.21 ± 0.52 mmol/L, P = 0.026). Each group showed a neutral effect on total cholesterol, lipoprotein A, apolipoprotein B, and fasting insulin levels. No cardiovascular and venous thromboembolic events occurred in the three groups.

CONCLUSIONSAmong Chinese postmenopausal women, half-dose CEE was not sufficient to induce a favorable lipid and carbohydrate profile compared with standard-dose CEE. Adding natural MP may counterbalance the TG-increasing effect of CEE.

TRIAL REGISTRATIONClinicalTrials.gov, NCT01698164; https://clinicaltrials.gov/ct2/show/NCT01698164?term=NCT01698164&rank=1.

Apolipoproteins B ; blood ; Blood Pressure ; drug effects ; Body Composition ; drug effects ; Dydrogesterone ; administration & dosage ; therapeutic use ; Estrogens, Conjugated (USP) ; administration & dosage ; therapeutic use ; Female ; Humans ; Insulin ; blood ; Lipoprotein(a) ; blood ; Metabolic Syndrome ; blood ; drug therapy ; Middle Aged ; Postmenopause ; Progesterone ; administration & dosage ; therapeutic use ; Triglycerides ; blood

In female sexual dysfunction (FSD), psychological and contextual factors significantly influence organic components of sexual response and behavior. The hormonal environment also affects FSD. Therefore, a tailored medical approach to each individual's sexual symptom is inevitable. This paper reviews currently available pharmacological treatment of FSD including the most recent advances and future targets in pharmacotherapy. In hormonal therapies for FSD, efficacy of estrogens and androgens on the treatment of vaginal atrophy, low sexual desire, and small subsets of genital arousal disorder, respectively, have been demonstrated. However, we need more data regarding long-term safety. There are two non-hormonal agents approved by the US Food and Drug Administration. Flibanserin has shown marginal benefit over placebo for the treatment of hypoactive sexual desire disorder. Ospemifen has shown beneficial effect on vulvovaginal pain from hormone related atrophy although it requires a longer period data to assess safety in other female genital organs, such as uterus and ovaries. Controversies still remain regarding hormonal therapies for FSD. Besides, some of the developing drugs still require more reliable safety and efficacy data. However, pharmacologic treatment of FSD is a promising field yet to be explored.
Androgens ; Arousal ; Atrophy ; Drug Therapy ; Estrogens ; Female* ; Genitalia, Female ; Humans ; Ovary ; Sexual Dysfunctions, Psychological ; United States Food and Drug Administration ; Uterus

Oseltamivir has been used as a worldwide preparation for treatment of influenza A and B including H1N1. Gastrointestinal discomforts as like nausea, vomiting are commonly reported but acute hemorrhagic colitis is a very rare adverse effect. We report a case of a 17-year-old male who showed abdominal pain, diarrhea and hematochezia after the second administration of oseltamivir. Computed tomography revealed continuous, circumferential and edematous wall thickening involving ascending to descending colon with pericolic infiltration. Colonoscopic examination revealed diffuse mucosal edema, congestion and friability, suggesting hemorrhagic colitis. Histopathological examination showed ischemia and focal loss of the crypts. It also showed hyalinization and minimal inflammatory cell infiltration in the lamina propria, consistent with acute to subacute ischemic colitis. This report is the first case of oseltamivir-related ischemic colitis proved by both endoscopic examination and pathologic findings in the patient who had no risk factor of ischemic colitis in Korea.
Abdominal Pain ; Administration, Oral* ; Adolescent ; Colitis* ; Colitis, Ischemic ; Colon, Descending ; Diarrhea ; Edema ; Estrogens, Conjugated (USP) ; Gastrointestinal Hemorrhage ; Humans ; Hyalin ; Influenza, Human ; Ischemia ; Korea ; Male ; Mucous Membrane ; Nausea ; Oseltamivir* ; Risk Factors ; Vomiting

OBJECTIVES: This study was conducted to examine the effects of hormone therapy on serum lipid levels in postmenopausal Korean women. METHODS: This retrospective cohort study included 154 healthy postmenopausal Korean women. Seventy-nine women took oral estrogen (conjugated equine estrogen 0.625 mg/day or equivalent), and 75 applied estrogen transdermally using 0.1% 17beta-estradiol gel. Micronized progesterone (MP) was added to 40 women of oral group and 49 women in transdermal group. Serum levels of triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and lipoprotein (a) were measured before, 3 and 6 month after hormone therapy. RESULTS: At baseline, mean body mass index (BMI) were lower (22.76 vs. 23.74 kg/m2) and proportion of family history of cardiovascular disease (CVD) (61 vs. 39%) were higher in oral group. In oral group, LDL-C and lipoprotein(a) levels decreased, and triglyceride and HDL-C levels increased significantly after 3 and 6 months. There was no significant change in lipoprotein levels compared to the baseline in transdermal group. There were also no differences with additional MP. Changing pattern of HDL-C during 6 months was significantly different by the route of estrogen administration. CONCLUSION: Oral estrogen therapy might be more beneficial than transdermal estrogen in terms of lipid in postmenopausal Korean women. The estrogen effects are not influenced by adding MP.
Body Mass Index ; Cardiovascular Diseases ; Cholesterol ; Cohort Studies ; Drug Administration Routes ; Estrogens ; Female ; Hormone Replacement Therapy ; Humans ; Lipoprotein(a) ; Lipoproteins ; Progesterone ; Retrospective Studies ; Triglycerides

Oestrogen is essential for maintaining bone mass, and it has been demonstrated to induce osteoblast proliferation and bone formation. In this study, complementary DNA (cDNA) microarrays were used to identify and study the expression of novel genes that may be involved in MC3T3-E1 cells' response to 17-β estradiol. MC3T3-E1 cells were inoculated in minimum essential media alpha (α-MEM) cell culture supplemented with 17-β estradiol at different concentrations and for different time periods. MC3T3-E1 cells treated with 10⁻⁸ mol⋅L⁻¹ 17-β estradiol for 5 days exhibited the highest proliferation and alkaline phosphatase (ALP) activity; thus, this group was chosen for microarray analysis. The harvested RNA was used for microarray hybridisation and subsequent real-time reverse transcription polymerase chain reaction (RT-PCR) to validate the expression levels for selected genes. The microarray results were analysed using both functional and pathway analysis. In this study, microarray analysis detected 5403 differentially expressed genes, of which 1996 genes were upregulated and 3407 genes were downregulated, 1553 different functional classifications were identified by gene ontology (GO) analysis and 53 different pathways were involved based on pathway analysis. Among the differentially expressed genes, a portion not previously reported to be associated with the osteoblast response to oestrogen was identified. These findings clearly demonstrate that the expression of genes related to osteoblast proliferation, cell differentiation, collagens and transforming growth factor beta (TGF-β)-related cytokines increases, while the expression of genes related to apoptosis and osteoclast differentiation decreases, following the exposure of MC3T3-E1 cells to α-MEM supplemented with 17-β estradiol. Microarray analysis with functional gene classification is critical for a complete understanding of complementary intracellular processes. This microarray analysis provides large-scale gene expression data that require further confirmatory studies.
3T3 Cells ; Alkaline Phosphatase ; drug effects ; Animals ; Apoptosis ; drug effects ; genetics ; Cell Culture Techniques ; Cell Differentiation ; drug effects ; genetics ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; genetics ; Collagen ; drug effects ; genetics ; Coloring Agents ; Cytokines ; drug effects ; genetics ; Estradiol ; administration & dosage ; pharmacology ; Estrogens ; administration & dosage ; pharmacology ; Gene Expression Profiling ; Mice ; Oligonucleotide Array Sequence Analysis ; Osteoblasts ; drug effects ; Signal Transduction ; drug effects ; genetics ; Tetrazolium Salts ; Thiazoles ; Transforming Growth Factor beta ; drug effects ; genetics