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After surgical or natural menopause, women face a high risk of nonalcoholic fatty liver disease (NAFLD), which can be diminished by hormone replacement therapy (HRT). The gut microbiota is subject to modulation by various physiological changes and the progression of diseases. This microbial ecosystem coexists symbiotically with the host, playing pivotal roles in immune maturation, microbial defense mechanisms, and metabolic functions essential for nutritional and hormone homeostasis. E2 supplementation effectively prevented the development of NAFLD after bilateral oophorectomy (OVX) in female rats. The changes in the gut microbiota such as abnormal biosynthetic metabolism of fatty acids caused by OVX were partially restored by E2 supplementation. The combination of liver transcriptomics and metabolomics analysis revealed that linoleic acid (LA) metabolism, a pivotal pathway in fatty acids metabolism was mainly manipulated during the induction and treatment of NAFLD. Further correlation analysis indicated that the gut microbes were associated with abnormal serum indicators and different LA metabolites. These metabolites are also closely related to serum indicators of NAFLD. An in vitro study verified that LA is an inducer of hepatic steatosis. The changes in transcription in the LA metabolism pathway could be normalized by E2 treatment. The metabolic perturbations of LA may directly and secondhand impact the development of NAFLD in postmenopausal individuals. This research focused on the sex-specific pathophysiology and treatment of NAFLD, providing more evidence for HRT and calling for the multitiered management of NAFLD.
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Premature menopause is associated with an increased prevalence of nonalcoholic fatty liver disease (NAFLD). Menopausal hormone therapy (MHT) has been widely used in clinical practice and has the potential to protect mitochondrial function and alleviate NAFLD. After bilateral oophorectomy (OVX), female rats without 17ß-estradiol (E2) intervention developed NAFLD, whereas E2 supplementation was effective in preventing NAFLD in female rats. The altered pathways and cellular events from both comparison pairs, namely, the OVX vs. sham group and the OVX vs. E2 group, were assessed using transcriptomic analysis. KEGG pathways enriched by both transcriptomic and metabolomic analyses strongly suggest that oxidative phosphorylation is a vital pathway that changes during the development of NAFLD and remains unchanged when E2 is applied. Liver tissue from the OVX-induced NAFLD group exhibited increased lipid peroxidation, impaired mitochondria, and downregulated ERα/SIRT1/PGC-1α expression. An in vitro study indicated that the protective effect of E2 treatment on hepatic steatosis could be abolished when ERα or SIRT1 was selectively inhibited. This damage was accompanied by reduced mitochondrial complex activity and increased lipid peroxidation. The current research indicates that E2 upregulates the ERα/SIRT1/PGC-1α signaling pathway and protects mitochondrial function to prevent OVX-induced NAFLD.
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BACKGROUND: Accumulating observational studies have identified associations between type 1 diabetes (T1D) and polycystic ovary syndrome (PCOS). Still, the evidence about the causal effect of this association is uncertain. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to test for the causal association between T1D and PCOS using data from a large-scale biopsy-confirmed genome-wide association study (GWAS) in European ancestries. We innovatively divided T1D into nine subgroups to be analyzed separately, including: type1 diabetes wide definition, type1 diabetes early onset, type 1 diabetes with coma, type 1 diabetes with ketoacidosis, type 1 diabetes with neurological complications, type 1 diabetes with ophthalmic complications, type 1 diabetes with peripheral circulatory complications, type 1 diabetes with renal complications, and type 1 diabetes with other specified/multiple/unspecified complications. GWAS data for PCOS were obtained from a large-scale GWAS (10,074 cases and 103,164 controls) for primary analysis and the IEU consortium for replication and meta-analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. RESULTS: Following rigorous instrument selection steps, the number of SNPs finally used for T1D nine subgroups varying from 6 to 36 was retained in MR estimation. However, we did not observe evidence of causal association between type 1 diabetes nine subgroups and PCOS using the IVW analysis, MR-Egger regression, and weighted median approaches, and all P values were > 0.05 with ORs near 1. Subsequent replicates and meta-analyses also yielded consistent results. A number of sensitivity analyses also did not reveal heterogeneity and pleiotropy, including Cochran's Q test, MR-Egger intercept test, MR-PRESSO global test, leave-one-out analysis, and funnel plot analysis. CONCLUSION: This is the first MR study to investigate the causal relationship between type 1 diabetes and PCOS. Our findings failed to find substantial causal effect of type 1 diabetes on risk of PCOS. Further randomized controlled studies and MR studies are necessary.
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Diabetes Mellitus Tipo 1 , Síndrome do Ovário Policístico , Feminino , Humanos , Biópsia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Olho , Estudo de Associação Genômica Ampla , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/genética , Análise da Randomização MendelianaRESUMO
Polycystic ovary syndrome (PCOS) is a prevalent reproductive endocrine disorder, with metabolic abnormalities and ovulation disorders. The post-translational modifications (PTMs) are functionally relevant and strengthen the link between metabolism and cellular functions. Lysine crotonylation is a newly identified PTM, the function of which in PCOS has not yet been reported. To explore the molecular mechanisms of crotonylation involved in the abnormalities of metabolic homeostasis and oocyte maturation in PCOS, by using liquid chromatography-tandem mass spectrometry analysis, we constructed a comprehensive map of crotonylation modifications in ovarian tissue of PCOS-like mouse model established by dehydroepiandrosterone induction. The crotonylation levels of proteins involved in metabolic processes were significantly decreased in PCOS ovaries compared to control samples. Further investigation showed that decrotonylation of Lon protease 1 (LONP1) at lysine 390 was associated with mitochondrial dysfunction in PCOS. Moreover, LONP1 crotonylation levels in PCOS were correlated with ovarian tissue oxidative stress levels, androgen levels, and oocyte development. Consistently, down-regulation of LONP1 and LONP1 crotonylation levels were also observed in the blood samples of PCOS patients. Collectively, our study revealed a mechanism by which the decrotonylation of LONP1 may attenuate its activity and alter follicular microenvironment to affect oocyte maturation in PCOS.
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BACKGROUND: This multi-center, cross-sectional study intended to explore the prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with polycystic ovary syndrome (PCOS). METHODS: Patients who met the PCOS Rotterdam diagnostic criteria were enrolled in 6 centers in China, and age-matched healthy volunteers were also recruited. Data were collected including medical history, physical characteristics, and blood tests (liver function, blood lipids, blood glucose and insulin, sex hormones, etc.). Transvaginal or transrectal ultrasound was employed to identify polycystic ovarian morphology (PCOM). The serological score Liver Fat Score (LFS) >-0.640 was used for the diagnosis of NAFLD, and the diagnosis of MAFLD was made according to the 2020 new definition. RESULTS: A total of 217 PCOS patients and 72 healthy controls were included. PCOS patients had impaired glucose and lipid metabolism, higher liver enzymes and LFS. Both NAFLD (33.6%) and MAFLD (42.8%) was more prevalent in PCOS patients than in controls (4.2%, P < 0.001). Logistic regression results showed that HOMA-IR ≥ 3.54 and ALT ≥ 18.2 were independently associated with NAFLD (P < 0.001) and MAFLD (P ≤ 0.001). The prevalence of NAFLD was significantly higher in PCOS patients with free androgen index (FAI) > 8 (53.8% versus 17.4%, P < 0.001) and BMI ≥ 24 kg/m2 (57.3%, 11.3%, P < 0.001). CONCLUSION: The prevalence of NAFLD/MAFLD in PCOS patients was significantly higher than that in healthy controls and was independently associated with HOMA-IR and ALT. PCOS patients with overweight and elevated FAI have a higher prevalence of fatty liver.
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Hepatopatia Gordurosa não Alcoólica , Síndrome do Ovário Policístico , Humanos , Feminino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Estudos Transversais , Fatores de RiscoRESUMO
BACKGROUND: This study aimed to evaluate the predictive value of the initial screening characteristics of women with anovulatory polycystic ovary syndrome (PCOS) who did or did not respond to 2.5 mg letrozole (LET). METHODS: The clinical and laboratory characteristics of women with PCOS who underwent LET treatment were evaluated. Women with PCOS were stratified according to their responses to LET (2.5 mg). The potential predictors of their responses to LET were estimated using logistic regression analysis. RESULTS: Our retrospective study included 214 eligible patients with a response to 2.5 mg LET (n = 131) or no response to 2.5 mg LET (n = 83). PCOS patients who responded to 2.5 mg LET showed better outcomes than those who did not (2.5 mg LET) for pregnancy rate, live birth rate, pregnancy rate per patient, and live birth rate per patient. Logistic regression analyses showed that late menarche (odds ratio [OR], 1.79 [95% confidence intervals (CI), 1.22-2.64], P = 0.003), and increased anti-müllerian hormone (AMH) (OR, 1.12 [95% CI, 1.02-1.23], P = 0.02), baseline luteinizing hormone (LH)/ follicle stimulating hormone (FSH) (OR, 3.73 [95% CI, 2.12-6.64], P < 0.001), and free androgen index (FAI) (OR, 1.37 [95% CI, 1.16-1.64], P < 0.001) were associated with a higher possibility of no response to 2.5 mg LET. CONCLUSIONS: PCOS patients with an increased LH/FSH ratio, AMH, FAI, and late menarche may need an increased dosage of LET for a treatment response, which could be helpful in designing a personalized treatment strategy.
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Síndrome do Ovário Policístico , Gravidez , Feminino , Humanos , Letrozol/uso terapêutico , Síndrome do Ovário Policístico/complicações , Estudos Retrospectivos , Fármacos para a Fertilidade Feminina/uso terapêutico , Hormônio Foliculoestimulante , Indução da Ovulação , Hormônio LuteinizanteRESUMO
BACKGROUND: To assess the correlation between clinical and biochemical hyperandrogenism parameters in polycystic ovary syndrome (PCOS) according to age. METHODS: This prospective study included 256 PCOS patients diagnosed according to the Rotterdam criteria in a university-based hospital. Androgen levels were measured using liquid chromatography-tandem mass spectrometry. Hirsutism, acne, and alopecia were assessed using the modified Ferriman-Gallwey (mF-G) score, Comprehensive Acne Severity Scale (CASS), and the Ludwig scale, respectively. The correlation between biochemical and clinical hyperandrogenism parameters was assessed in younger and older women with PCOS. RESULTS: The 256 PCOS patients were classified by age into two groups: age 18-29 years (n = 151) and age 30-40 years (n = 84). In women with PCOS, mF-G was significantly positively correlated with the free androgen index (FAI), dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S). CASS had a significant positive correlation with DHEA. mF-G was positively correlated with FAI in those aged 18-29 years, but the correlations were not significant in those aged 30-40 years. The positive correlation between specific body regions of clinical hyperandrogenism, especially mF-G of chin, lower abdomen, and thighs, and testosterone, as well as with FAI, was highest in those aged 18-29 years. In those aged 30-40 years clinical hyperandrogenism was mainly affected by DHEA, DHEA-S, and dihydrotestosterone. CONCLUSION: The correlation between biochemical and clinical hyperandrogenism parameters varied with age in our East Asian population. Clinical hyperandrogenism was positively correlated with FAI in younger women with PCOS. The correlation between biochemical and clinical hyperandrogenism was not significant in older women with PCOS.
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Acne Vulgar , Hiperandrogenismo , Síndrome do Ovário Policístico , Feminino , Humanos , Idoso , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/diagnóstico , Androgênios , Estudos Prospectivos , Hiperandrogenismo/complicações , Testosterona , Acne Vulgar/epidemiologia , DesidroepiandrosteronaRESUMO
Ovariectomy (OVX) conducted before the onset of natural menopause is considered to bringing forward and accelerate the process of ageing-associated neurodegeneration. However, the mechanisms underlying memory decline and other cognitive dysfunctions following OVX are unclear. Given that iron accumulates during ageing and after OVX, we hypothesized that excess iron accumulation in the hippocampus would cause ferroptosis-induced increased neuronal degeneration and death associated with memory decline. In the current study, female rats that underwent OVX showed decreased dihydroorotate dehydrogenase (DHODH) expression and reduced performance in the Morris water maze (MWM). We used primary cultured hippocampal cells to explore the ferroptosis resistance-inducing effect of 17ß-oestradiol (E2). The data supported a vital role of DHODH in neuronal ferroptosis. Specifically, E2 alleviated ferroptosis induced by erastin and ferric ammonium citrate (FAC), which can be blocked by brequinar (BQR). Further in vitro studies showed that E2 reduced lipid peroxidation levels and improved the behavioural performance of OVX rats. Our research interprets OVX-related neurodegeneration with respect to ferroptosis, and both our in vivo and in vitro data show that E2 supplementation exerts beneficial antiferroptotic effects by upregulating DHODH. Our data demonstrate the utility of E2 supplementation after OVX and provide a potential target, DHODH, for which hormone therapy has not been available.
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Di-Hidro-Orotato Desidrogenase , Ferroptose , Animais , Feminino , Ratos , Estradiol/farmacologia , Estradiol/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/metabolismo , Ovariectomia/efeitos adversosRESUMO
Objective: To assess the effect of antiandrogenic pretreatment using combined oral contraceptives (COCs) before ovulation induction in infertile patients with polycystic ovary syndrome (PCOS) with hyperandrogenism. Design: Prospective, randomized open-labeled cohort study. Setting: Multicenter. Patients: PCOS patients with hyperandrogenism and requiring infertility treatments. Interventions: Randomization to direct ovulation induction of letrozole (letrozole group) or ethinylestradiol/cyproterone acetate (EE/CPA) for 3 months and subsequent letrozole-induced ovulation (EE/CPA+ letrozole group). The maximum number of ovulation induction cycle was three to four. Main Outcome Measures: Ovulation rate, conception rate, ongoing pregnancy rate, and live birth rate were the main outcomes of the study. Results: There were no significant differences in the cumulative ovulation, conception, ongoing pregnancy, and live birth rates between the letrozole and EE/CPA+ letrozole groups (cumulative ovulation: 206/254 [81.10%] vs. 169/205 [82.44%], risk ratio [RR]= 1.09 [0.68,1.76], P=0.713; conception: 44/90 [48.89%] vs. 42/76 [55.26%], RR= 1.29 [0.70,2.38], P=0.413; ongoing pregnancy: 33/90 [36.67%] vs. 33/76 [43.42%], RR=1.33 [0.71,2.47], P=0.376; and live birth: 32/90 [35.56%] vs. 31/76 [40.79%], RR=1.25 [0.67, 2.34], P=0.489). Conclusions: The results of this study showed that COC pretreatment was not superior to direct letrozole-induced ovulation therapy in improving ovulation and pregnancy results in women with PCOS. There is no benefit to perform antiandrogenic therapy before ovulation induction in patients with PCOS in clinical practice. Clinical Trial Registration: www.clinicaltrials.gov, identifier ChiCTR1900022839.
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Hiperandrogenismo , Infertilidade Feminina , Síndrome do Ovário Policístico , Clomifeno , Estudos de Coortes , Feminino , Fármacos para a Fertilidade Feminina , Humanos , Hiperandrogenismo/complicações , Hiperandrogenismo/tratamento farmacológico , Infertilidade Feminina/tratamento farmacológico , Infertilidade Feminina/terapia , Letrozol , Masculino , Indução da Ovulação/métodos , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/tratamento farmacológico , Gravidez , Estudos ProspectivosRESUMO
Background: Previous studies demonstrated that miRNA-1827 could repress various cancers on proliferation, angiogenesis, and metastasis. However, little attention has been paid to its role in ovarian cancer as a novel biomarker or intervention target, especially its clinical significance and underlying regulatory network. Methods: A meta-analysis of six microarrays was adopted here to determine the expression trend of miRNA-1827, and was further validated by gene expression profile data and cellular experiments. We explored the functional annotations through enrichment analysis for the differentially expressed genes targeted by miRNA-1827. Subsequently, we identified two hub genes, SPTBN2 and BCL2L1, based on interaction analysis using two online archive tools, miRWALK (it consolidates the resources of 12 miRNA-focused servers) and Gene Expression Profiling Interactive Analysis (GEPIA). Finally, we validated their characteristics and clinical significance in ovarian cancer. Results: The comprehensive meta-analysis revealed that miRNA-1827 was markedly downregulated in clinical and cellular specimens. Transfection of the miRNA-1827 mimic could significantly inhibit cellular proliferation. Concerning its target genes, they were involved in diverse biological processes related to tumorigenesis, such as cell proliferation, migration, and the apoptosis signaling pathway. Moreover, interaction analysis proved that two hub genes, SPTBN2 and BCL2L1, were highly associated with poor prognosis in ovarian cancer. Conclusion: These integrated bioinformatic analyses indicated that miRNA-1827 was dramatically downregulated in ovarian cancer as a tumor suppressor. The upregulation of its downstream modulators, SPTBN2 and BCL2L1, was associated with an unfavorable prognosis. Thus, the present study has identified miRNA-1827 as a potential intervention target for ovarian cancer based on our bioinformatic analysis processes.
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BACKGROUND: Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy that affects reproduction and metabolism. Mammalian target of rapamycin (mTOR) has been shown to participate in female reproduction under physiological and pathological conditions. This study aimed to investigate the role of mTOR complex 1 (mTORC1) signaling in dehydroepiandrosterone (DHEA)-induced PCOS mice. RESULTS: Female C57BL/6J mice were randomly assigned into three groups: control group, DHEA group, and DHEA + rapamycin group. All DHEA-treated mice were administered 6 mg/100 g DHEA for 21 consecutive days, and the DHEA + rapamycin group was intraperitoneally injected with 4 mg/kg rapamycin every other day for the last 14 days of the DHEA treatment. There was no obvious change in the expression of mTORC1 signaling in the ovaries of the control and DHEA groups. Rapamycin did not protect against DHEA-induced acyclicity and PCO morphology, but impeded follicle development and elevated serum testosterone levels in DHEA-induced mice, which was related with suppressed Hsd3b1, Cyp17a1, and Cyp19a1 expression. Moreover, rapamycin also exacerbated insulin resistance but relieved lipid metabolic disturbance in the short term. CONCLUSIONS: Rapamycin exacerbated reproductive imbalance in DHEA-induced PCOS mice, which characterized by elevated testosterone levels and suppressed steroid synthesis. This underscores the need for new mTORC1-specific and tissue-specific mTOR-related drugs for reproductive disorders.
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Desidroepiandrosterona/efeitos adversos , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Reprodução/efeitos dos fármacos , Sirolimo/efeitos adversos , Testosterona/efeitos adversos , Animais , Modelos Animais de Doenças , Feminino , Humanos , CamundongosRESUMO
Premature ovarian insufficiency (POI) is a heterogeneous disorder and lacks effective interventions in clinical applications. This research aimed to elucidate the potential effects of recombinant human PEGylated growth hormone (rhGH) on follicular development and mitochondrial function in oocytes as well as ovarian parameters in POI rats induced by the chemotherapeutic agent. The impacts of rhGH on ovarian function before superovulation on follicles, estrous cycle, and sex hormones were evaluated. Oocytes were retrieved to determine oocyte quality and oxidative stress parameters. Single-cell sequencing was applied to investigate the latent regulatory network. This study provides new evidence that a high dosage of rhGH increased the number of retrieved oocytes even though it did not completely restore the disturbed estrous cycle and sex hormones. rhGH attenuated the apoptosis of granulosa cells and oxidative stress response caused by reactive oxygen species (ROS) and mitochondrial superoxide. Additionally, rhGH modulated the energy metabolism of oocytes concerning the mitochondrial membrane potential and ATP content but not mtDNA copy numbers. Based on single-cell transcriptomic analysis, we found that rhGH directly or indirectly promoted the balance of oxidative stress and cellular oxidant detoxification. Four hub genes, Pxmp4, Ehbp1, Mt-cyb, and Enpp6, were identified to be closely related to the repair process in oocytes as potential targets for POI treatment.
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Study objective: To generate and validate nomograms to predict any-stage and stage III-IV endometriosis before surgery in infertile women. Design: A single center retrospective cohort study. Setting: University affiliated hospital. Patients: Infertile patients (n = 1,016) who underwent reproductive surgery between July 1, 2016 and June 30, 2019. Interventions: None. Main outcome measurements: We randomly selected 2/3 of the included patients (667 patients, training sample) to analyze and generate predictive models and validated the models on the remaining patients (339 patients, validation sample). A multivariate logistic regression model was used with the training sample to select variables using a back stepwise procedure. Nomograms to predict any-stage and stage III-IV endometriosis were constructed separately. The discriminations and calibrations of both nomograms were tested on the overall population and a subgroup without endometrioma diagnosed on transvaginal sonography (TVS) of training and validation samples. The impact of different variables in these models was evaluated. Results: There were 377 (55.7%) women in the training sample and 196 (57.8%) in the validation sample who were diagnosed with endometriosis. The nomogram predicting any-stage endometriosis had an area under the curve (AUC) of 0.760 for the training sample and 0.744 for the validation sample, with favorable calibrations in the overall population. However, the performance was significantly decreased in patients without endometrioma on TVS, with an AUC of 0.726 in the training sample and 0.694 in the validation sample. Similarly, the nomogram predicting stage III-IV endometriosis had an AUC of 0.833 and 0.793 for the training and validation samples, respectively, as well as a favorable calibration. However, the performance of the nomogram on patients without endometrioma on TVS was poor. Endometrioma on TVS strongly predicted both any stage and stage III-IV endometriosis on both samples. Conclusion: We developed nomograms to predict any-stage and stage III-IV endometriosis but their performance were significantly decreased in patients without endometrioma on TVS. Endometrioma on TVS strongly predicted any and III-IV stage endometriosis in both sample groups. Therefore, we recommend that this study be used as encouragement to advance the utilization of advanced imaging for endometriosis for better clinical prognosis.
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OBJECTIVE: Endometriosis is a common gynecologic disease that frequently leading to chronic pelvic pain, severe dysmenorrhea, and subfertility. As first-line hormonal treatment can interfere with ovulation and may cause recurrent pelvic pain, exploration of new non-hormonal therapeutic approaches becomes increasingly necessary. This review aimed to evaluate the pre-clinical and clinical efficacy and safety of non-hormonal treatment for endometriosis DATA SOURCES:: Databases including PubMed, Embase, Cochrane Library, SINOMED, ClinicalTrials.gov, and Google Scholar were searched up to October 2019, using search terms "endometriosis" and "non-hormonal therapy." STUDY SELECTION: Twenty-four articles were reviewed for analysis, including nine animal studies and 15 human trials; all were published in English. RESULTS: Twenty-four articles were identified, including 15 human trials with 861 patients and nine animal studies. Some agents have been evaluated clinically with significant efficacy in endometriosis-related pelvic pain and subfertility, such as rofecoxib, etanercept, pentoxifylline, N-palmitoylethanolamine, resveratrol, everolimus, cabergoline (Cb2), and simvastatin. Other drugs with similar pharmacological properties, like parecoxib, celecoxib, endostatin, rapamycin, quinagolide, and atorvastatin, have only been tested in animal studies. CONCLUSIONS: Clinical data about most of the non-hormonal agents are not sufficient to support them as options for replacement therapy for endometriosis. In spite of this, a few drugs like pentoxifylline showed strong potential for real clinical application.
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Endometriose/tratamento farmacológico , Animais , Catequina/análogos & derivados , Catequina/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resveratrol/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase of the phosphatidylinositol kinase-related kinase family that regulates cell growth, metabolism, and autophagy. Extensive research has linked mTOR to several human diseases including cancer, neurodegenerative disorders, and aging. In this review, recent publications regarding the mechanisms underlying the role of mTOR in female reproduction under physiological and pathological conditions are summarized. Moreover, we assess whether strategies to improve or suppress mTOR expression could have therapeutic potential for reproductive diseases like premature ovarian failure, polycystic ovarian syndrome, and endometriosis.
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BACKGROUND: Turner syndrome (TS) is a common chromosomal disorder affecting approximately 1:2,500 live female births. Mosaic 47,XXX karyotype is found in 3%-4% of TS patients. TS phenotype in rare 45,X/47,XXX mosaicism patients is milder than in classic TS, however their ovarian function, especially in the mature age, has not been described in detail. METHODS: A case report and literature review. RESULTS: A 30-year-old woman with menstrual irregularity and primary infertility presented with short stature and multiple nevi on the face without other common TS clinical features. She had spontaneous puberty and menarche but diminished ovarian reserve at the age of 30. Fluorescence in situ hybridization (FISH) indicated 45,X/47,XXX mosaicism, which was once misdiagnosed as 45,X monosomy. Literature review revealed the prevalence of short stature in only 64.3% of 45,X/47,XXX mosaicism cases, that is, much less frequently than in pure 45,X monosomy. The risk of premature ovarian insufficiency in 45,X/47,XXX mosaicism patients is higher, and ovarian failure is usually observed at around 30 years of age. CONCLUSION: FISH should be recommended to evaluate low proportion mosaicism in similar cases. Due to the risk of ovarian failure, fertility preservation for patients with 45,X/47,XXX mosaicism at a younger age must be considered.
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Reserva Ovariana/genética , Síndrome de Turner/genética , Adulto , Cromossomos Humanos X/genética , Feminino , Humanos , Cariótipo , Cariotipagem/métodos , Mosaicismo , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/genéticaRESUMO
Decline in successful conception decreases more rapidly after 38 years of age owing to follicular depletion and decreased oocyte quality. However, limited information is available regarding the underlying mechanism and the useful treatment. This study aimed to evaluate the effects of growth hormone supplementation on oocyte maturation in vivo in aged and young mice and to determine its effect on mitochondrial function. The influence of three different doses of recombinant human growth hormone (rhGH) (0.4, 0.8 and 1.6 mg/kg/day) for 8 weeks before ovarian stimulation was analyzed. Superovulated oocytes were released from the oviduct of 12-week-old and 40-week-old female C57BL/6J mice 14-16 h after administration of human chorionic gonadotropin. Ovarian follicle and morphological analysis and oocyte maturation parameters were then evaluated. This study is the first, to our knowledge, to report that medium- and high-dose rhGH significantly increases antral follicles in aged mice but anti-Müllerian hormone (AMH) levels. Furthermore, derived oocytes, MII-stage oocyte rate, ATP levels, mitochondrial membrane potential and frequencies of homogeneous mitochondrial distribution increased. In contrast, in both aged and young mice, the mtDNA copy numbers per oocyte were similar before rhGH administration, and upon saline administration, they did not differ significantly. We conclude that medium-dose rhGH supplementation before standard ovarian stimulation regimens improves oocyte quality in aged mice, probably by enhancing mitochondrial functionality.