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1.
J Clin Med ; 10(22)2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34830617

RESUMO

Hysterectomy is the most common treatment option in women with uterine fibroids, providing definitive relief from the associated burdensome symptoms. As with all surgical interventions, hysterectomy is associated with risk of complications, short-term morbidities, and mortality, all of which have been described previously. However, information on the potential long-term risks of hysterectomy is only recently becoming available. A systematic literature review was performed to identify studies published between 2005 and December 2020 evaluating the long-term impact of hysterectomy on patient outcomes. A total of 29 relevant studies were identified. A review of the articles showed that hysterectomy may increase the risk of cardiovascular events, certain cancers, the need for further surgery, early ovarian failure and menopause, depression, and other outcomes. It is important to acknowledge that the available studies examine possible associations and hypotheses rather than causality, and there is a need to establish higher quality studies to truly evaluate the long-term consequences of hysterectomy. However, it is of value to consider these findings when discussing the benefits and risks of all treatment options with patients with uterine fibroids to allow for preference-based choices to be made in a shared decision-making process. This is key to ensuring that patients receive the treatment that best meets their individual needs.

2.
Endocr Rev ; 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34741454

RESUMO

Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or non-invasive treatment option exists for hormone-dependent uterine fibroids due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on their risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and uterine fibroids' complexity can contribute to the newer targeted therapies.

3.
J Adv Pharm Res ; 5(2): 260-275, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746367

RESUMO

Uterine fibroids (UFs) are the most prevalent gynecologic neoplasm, affecting 70-80% of women over their lifespan. Although UFs are benign they can become life-threatening and require invasive surgeries such as myomectomy and hysterectomy. Notwithstanding the significant negative influence UFs have on female reproductive health, very little is known about early events that initiate tumor development. Several risk factors for UFs have been identified including vitamin D deficiency, inflammation, DNA repair deficiency, and environmental exposures to endocrine-disrupting chemicals (EDCs). EDCs have come under scrutiny recently due to their role in UF development. Epidemiologic studies have found an association between increased risk for early UF diagnosis and in utero EDC exposure. Environmental exposure to EDCs during uterine development increases UF incidence in a UF animal model. Notably, several studies demonstrated that abnormal myometrial stem cells (MMSCs) are the cell origin for UFs development. Our recent studies demonstrated that early-life EDC exposure reprogrammed the MMSCs toward a pro-fibroid landscape and altered the DNA repair and inflammation pathways. Notably, Vitamin D3 (VITD3) as a natural compound shrank the UF growth concomitantly with the reversion of several abnormal biological pathways and ameliorated the developmental exposure-induced DNA damage and pro-inflammation pathway in primed MMSCs. This review highlights and emphasizes the importance of multiple pathway interactions in the context of hypovitaminosis D at the MMSCs level and provides proof-of-concept information that can help develop a safe, long-term, durable, and non-surgical therapeutic option for UFs.

4.
Reprod Sci ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642915

RESUMO

Uterine leiomyosarcoma (LMS) contributes to a significant proportion of uterine cancer deaths. It is a rare and high-risk gynecological cancer. LMS is challenging to the treatment due to the resistance of several therapies. The activation of the Hedgehog (HH) pathway has been reported in several types of female cancers. Uterine LMS presents an upregulation of the crucial HH signaling pathway members such as SMO and GLI1. Although targeting the HH pathway exhibited a potent inhibitory effect on the phenotype of uterine LMS in vitro, the effect of the HH inhibitors on LMS growth in vivo has not been identified. The present study aimed to assess the effect of Hedgehog pathway inhibitors (SMO-LDE225 and GLI-Gant61) as a therapeutic option in the xenograft model of uterine LMS. The results demonstrated that LDE225 treatment did not show any inhibitory effect on LMS tumor growth; however, treatment with GLI inhibitor (Gant61) induced a remarkable tumor regression with a significant decrease in Ki67 expression, compared to control (p < 0.01). Moreover, administration of Gant61 decreased the expression of GLI1, GLI target genes BMP4 and c-MYC (p < 0.05), indicating that the HH pathway is implicated in the LMS experimental model. In conclusion, our studies demonstrate for the first time that GLI inhibitor (Gant61), but not SMO inhibitor (LDE225), shows a potent inhibitory effect on LMS tumor growth and concomitantly suppresses the expression of GLI1- and GLI-targeted genes using the xenograft model of uterine LMS.

5.
Expert Opin Drug Saf ; : 1-10, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34612122

RESUMO

Introduction: Uterine fibroids (UFs) are the most prevalent benign neoplastic threat originating from myometria of reproductive age women, with a profound financial load valued in hundreds of billions of dollars. Unfortunately, there is no curative treatment so far except surgery and available pharmacological treatments are restricted for short-term treatment options. Thus, there is a large unmet need in the UF space for noninvasive therapeutics.Areas covered: The authors reviewed the literature available for the utility of gonadotropin-releasing hormone (GnRH) analogs in women with UFs. We also focused on clinical studies exploring the therapeutic benefits of novel oral non-peptide GnRH antagonists that were recently approved by the U.S. Food and Drug Administration (FDA) in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with UFs in premenopausal women.Expert opinion: The results regarding the efficacy of new-generation oral GnRH-antagonists, such as elagolix, relugolix and linzagolix, are promising and offer potential prospect for the future therapy of UFs. However, these antagonists must be combined with hormonal add-back therapy to minimize the resultant hypoestrogenic side effects such as bone loss.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34582715

RESUMO

Objective: To assess outcomes of women with uterine fibroids (UFs) and heavy menstrual bleeding (HMB) treated with 300 mg elagolix twice daily plus add-back therapy (E2 1 mg/NETA 0.5 mg once daily) or placebo who were not considered responders in pooled analysis of two phase 3, 6-month randomized clinical trials (Elaris UF-1 and UF-2). Methods: Responders were defined as women who met both primary end point bleeding criteria (<80 mL menstrual blood loss [MBL] during the final month and ≥50% reduction in MBL from baseline to the final month) and either completed the study or discontinued due to predefined reasons. Thus, women termed nonresponders who were analyzed in this study who met neither or one bleeding end point or met both criteria but prematurely discontinued treatment because of adverse events, perceived lack of efficacy, or required surgical or interventional treatment for UFs were analyzed in this study. This post hoc analysis assessed mean changes from baseline in MBL, as well as adverse events. Results: Among 367 women receiving elagolix with add-back with observed data, 89 (24%) were not considered responders. Within this subset, 17 (19%) women met both bleeding criteria but prematurely discontinued treatment for the reasons mentioned above, while 23 (26%) met one bleeding criterion and 49 (55%) met neither bleeding criteria, regardless of discontinuation status. Among all nonresponders, a numerical trend toward greater mean reductions in MBL was observed in those receiving elagolix with add-back, compared with placebo group nonresponders. No differences in adverse events were observed between responders and nonresponders. Conclusion: Forty of 89 (45%) women with HMB and UFs who were classified as nonresponders in the UF-1 or UF-2 trials may have had a clinically meaningful response to elagolix with add-back therapy because they met at least one of the objective bleeding criteria. Clinical Trial Registration: Clinicaltrials.gov, NCT02654054 and NCT02691494. (NEJM 2020; 382:328-340) DOI: 10.1056/NEJMoa1904351.

7.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502090

RESUMO

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Previous studies have demonstrated the therapeutic efficacy of human bone marrow mesenchymal stem cells (BM-hMSCs) for PCOS; however, the regulatory mechanism remains unknown. Bone morphogenetic proteins (BMPs) secreted by BM-hMSCs may underlie the therapeutic effect of these cells on PCOS, based on the ability of BMPs to modulate androgen production and alter steroidogenesis pathway enzymes. In this study, we analyze the effect of BMP-2 on androgen production and steroidogenic pathway enzymes in H295R cells as a human PCOS in vitro cell model. In H295R cells, BMP-2 significantly suppressed cell proliferation, androgen production, and expression of androgen-synthesizing genes, as well as inflammatory gene expression. Furthermore, H295R cells treated with the BM-hMSCs secretome in the presence of neutralizing BMP-2 antibody or with BMP-2 gene knockdown showed augmented expression of androgen-producing genes. Taken together, these results indicate that BMP-2 is a key player mediating the favorable effects of the BM-hMSCs secretome in a human PCOS cell model. BMP-2 overexpression could increase the efficacy of BM-hMSC-based therapy, serving as a novel stem cell therapy for patients with intractable PCOS.


Assuntos
Androgênios/metabolismo , Proteína Morfogenética Óssea 2/farmacologia , Síndrome do Ovário Policístico/metabolismo , Células Tecais/metabolismo , Adulto , Animais , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Exocitose , Feminino , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Células Tecais/efeitos dos fármacos , Células Tecais/fisiologia
8.
J Womens Health (Larchmt) ; 30(10): 1416-1430, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34435897

RESUMO

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457.


Assuntos
Densidade Óssea , Imidazóis , Feminino , Humanos , Lactação , Acetato de Medroxiprogesterona , Gravidez , Sulfonas
9.
Pharmacol Res ; 172: 105856, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34461224

RESUMO

Uterine leiomyomas or fibroids are the most common tumors of the female reproductive tract. Estrogen (E2), a steroid-derived hormone, and its receptors (ERs), particularly ER-α, are important drivers for the development and growth of leiomyomas. We previously demonstrated that simvastatin, a drug used for hyperlipidemia, also possesses anti-leiomyoma properties. The aim of this work is to investigate the impact of simvastatin on ER-α signaling in leiomyoma cells, including its expression, downstream signaling, transcriptional activity, post-translational modification, trafficking and degradation. Primary and immortalized human uterine leiomyoma (HuLM) cells were used for in vitro experiments. Immunodeficient mice xenografted with human leiomyoma tissue explants were used for in vivo studies. Leiomyoma samples were obtained from patients enrolled in an ongoing double-blinded, phase II, randomized controlled trial. Here, we found that simvastatin significantly reduced E2-induced proliferation and PCNA expression. In addition, simvastatin reduced total ER-α expression in leiomyoma cells and altered its subcellular localization by inhibiting its trafficking to the plasma membrane and nucleus. Simvastatin also inhibited E2 downstream signaling, including ERK and AKT pathways, E2/ER transcriptional activity and E2-responsive genes. To explain simvastatin effects on ER-α level and trafficking, we examined its effects on ER-α post-translational processing. We noticed that simvastatin reduced ER-α palmitoylation; a required modification for its stability, trafficking to plasma membrane, and signaling. We also observed an increase in ubiquitin-mediated ER-α degradation. Importantly, we found that the effects of simvastatin on ER-α expression were recapitulated in the xenograft leiomyoma mouse model and human tissues. Thus, our data suggest that simvastatin modulates several E2/ER signaling targets with potential implications in leiomyoma therapy and beyond.

10.
Stem Cell Res Ther ; 12(1): 388, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233746

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems. We evaluated the therapeutic efficacy of BM-hMSC and its secretome in both in vitro and in vivo PCOS models. METHODS: For in vitro experiment, we treated conditioned media from BM-hMSC to androgen-producing H293R cells and analyzed androgen-producing gene expression. For in vivo experiment, BM-hMSC were implanted into letrozole (LTZ)-induced PCOS mouse model. BM-hMSC effect in androgen-producing cells or PCOS model mice was assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (quantitative real-time polymerase chain reaction [qRT-PCR] and Western blot, animal tissue assay (H&E staining), and fertility by pup delivery. RESULTS: BM-hMSC significantly downregulate steroidogenic gene expression, curb inflammation, and restore fertility in treated PCOS animals. The anti-inflammatory cytokine interleukin-10 (IL-10) played a key role in mediating the effects of BM-hMSC in our PCOS models. We demonstrated that BM-hMSC treatment was improved in metabolic and reproductive markers in our PCOS model and able to restore fertility. CONCLUSION: Our study demonstrates for the first time the efficacy of intra-ovarian injection of BM-hMSC or its secretome to treat PCOS-related phenotypes, including both metabolic and reproductive dysfunction. This approach may represent a novel therapeutic option for women with PCOS. Our results suggest that BM-hMSC can reverse PCOS-induced inflammation through IL-10 secretion. BM-hMSC might be a novel and robust therapeutic approach for PCOS treatment.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Síndrome do Ovário Policístico , Animais , Feminino , Fertilidade , Humanos , Interleucina-10/genética , Camundongos , Síndrome do Ovário Policístico/terapia
11.
Front Cell Dev Biol ; 9: 633180, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113609

RESUMO

Uterine fibroids (leiomyomas) are the most common benign gynecological tumors in women of reproductive age worldwide. They cause heavy menstrual bleeding, usually leading to severe anemia, pelvic pain/pressure, infertility, and other debilitating morbidities. Fibroids are believed to be monoclonal tumors arising from the myometrium, and recent studies have demonstrated that fibroids actively influence the endometrium globally. Studies suggest a direct relationship between the number of fibroids removed and fertility problems. In this review, our objective was to provide a complete overview of the origin of uterine fibroids and the molecular pathways and processes implicated in their development and growth, which can directly affect the function of a healthy endometrium. One of the most common characteristics of fibroids is the excessive production of extracellular matrix (ECM) components, which contributes to the stiffness and expansion of fibroids. ECM may serve as a reservoir of profibrotic growth factors such as the transforming growth factor ß (TGF-ß) and a modulator of their availability and actions. Fibroids also elicit mechanotransduction changes that result in decreased uterine wall contractility and increased myometrium rigidity, which affect normal biological uterine functions such as menstrual bleeding, receptivity, and implantation. Changes in the microRNA (miRNA) expression in fibroids and myometrial cells appear to modulate the TGF-ß pathways and the expression of regulators of ECM production. Taken together, these findings demonstrate an interaction among the ECM components, TGF-ß family signaling, miRNAs, and the endometrial vascular system. Targeting these components will be fundamental to developing novel pharmacotherapies that not only treat uterine fibroids but also restore normal endometrial function.

12.
F S Sci ; 2(1): 88-100, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34124698

RESUMO

Scientists from multiple basic disciplines and an international group of physician-scientists from the field of obstetrics and gynecology presented recent studies and discussed new and evolving theories of uterine fibroid etiology, growth and development at The Basic Science of the Uterine Fibroids meeting, sponsored by the Campion Fund and the National Institute of Environmental Health Sciences. The purpose was to share up-to date knowledge and to stimulate new concepts regarding the basic molecular biology and pathophysiology of uterine fibroids, and to promote future collaborations. The meeting was held at the National Institutes of Environmental Health Sciences in North Carolina on February 28, 2020. Speakers reviewed recent advances in cellular and molecular processes that contribute to fibroid growth and new opportunities for treatment. At the conclusion of the conference, attendees identified important new directions for future research.

14.
Reprod Sci ; 28(6): 1688-1696, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33956339

RESUMO

Premature ovarian insufficiency (POI) is a condition characterized by amenorrhea, hypergonadotropic hypogonadism, estrogen deficiency, and reduced follicle counts leading to infertility under the age of 40. POI occurs in approximately 1-3% of women in the general population. Evaluation is warranted when the diagnosis of POI is made to rule out underlying etiologies, which could be multifactorial. This review serves to cover the novel treatment approaches reported in the literature.

15.
Sci Rep ; 11(1): 9371, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931688

RESUMO

Pathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs). An integrated proteogenomic analysis of ULMs from HLRCC (n = 16; FH-mutation confirmed) and non-syndromic (NS) patients (n = 12) identified a significantly higher protein:transcript correlation in HLRCC (R = 0.35) vs. NS ULMs (R = 0.242, MWU p = 0.0015). Co-altered proteins and transcripts (228) included antioxidant response element (ARE) target genes, such as thioredoxin reductase 1 (TXNRD1), and correlated with activation of NRF2-mediated oxidative stress response signaling in HLRCC ULMs. We confirm 185 transcripts previously described as altered between HLRCC and NS ULMs, 51 co-altered at the protein level and several elevated in HLRCC ULMs are involved in regulating cellular metabolism and glycolysis signaling. Furthermore, 367 S-(2-succino)cysteine peptides were identified in HLRCC ULMs, of which sixty were significantly elevated in HLRCC vs. NS ULMs (LogFC = 1.86, MWU p < 0.0001). These results confirm and define novel proteogenomic alterations in uterine leiomyoma tissues collected from HLRCC patients and underscore conserved molecular alterations correlating with inactivation of the FH tumor suppressor gene.


Assuntos
Biomarcadores Tumorais/análise , Fumarato Hidratase/genética , Predisposição Genética para Doença , Leiomiomatose/patologia , Mutação , Síndromes Neoplásicas Hereditárias/patologia , Proteogenômica/métodos , Proteoma/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Uterinas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Leiomiomatose/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Proteoma/análise , Neoplasias Cutâneas/metabolismo , Neoplasias Uterinas/metabolismo
17.
Nutrients ; 13(4)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918317

RESUMO

Diet and nutrition are fundamental in maintaining the general health of populations, including women's health. Health status can be affected by nutrient deficiency and vice versa. Gene-nutrient interactions are important contributors to health management and disease prevention. Nutrition can alter gene expression, as well as the susceptibility to diseases, including cancer, through several mechanisms. Gynecological diseases in general are diseases involving the female reproductive system and include benign and malignant tumors, infections, and endocrine diseases. Benign diseases such as uterine fibroids and endometriosis are common, with a negative impact on women's quality of life, while malignant tumors are among the most common cause of death in the recent years. In this comprehensive review article, a bibliographic search was performed for retrieving information about nutrients and how their deficiencies can be associated with gynecological diseases, namely polycystic ovary syndrome, infertility, uterine fibroids, endometriosis, dysmenorrhea, and infections, as well as cervical, endometrial, and ovarian cancers. Moreover, we discussed the potential beneficial impact of promising natural compounds and dietary supplements on alleviating these significant diseases.


Assuntos
Deficiências Nutricionais/terapia , Doenças dos Genitais Femininos/terapia , Terapia Nutricional/tendências , Deficiências Nutricionais/complicações , Deficiências Nutricionais/fisiopatologia , Feminino , Doenças dos Genitais Femininos/etiologia , Doenças dos Genitais Femininos/fisiopatologia , Humanos , Estado Nutricional
18.
Expert Rev Clin Pharmacol ; 14(4): 427-437, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33682578

RESUMO

INTRODUCTION: Uterine fibroids (UFs) are the most common benign tumor arising from myometrium of reproductive age women, with significant financial burden estimated in hundreds of billions of dollars. Unfortunately, there are limitations in available long-term treatment options. Thus, there is a large unmet need in the UF space for noninvasive therapeutics. AREAS COVERED: Authors reviewed the literature available for elagolix; an orally bioavailable, second-generation, non-peptide gonadotropin-releasing hormone (GnRH) antagonist recently approved by the US Food and Drug Administration (FDA) in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with UFs in premenopausal women. EXPERT OPINION: The utility of new-generation oral GnRH-antagonists, such as elagolix, relugolix and linzagolix, is offering a new potential opportunity for the future therapy of UFs: elagolix has been the most studied drug of this class for treating benign gynecological diseases, including endometriosis and UFs, for which it has been US FDA-approved in 2018 and 2020, respectively.


Assuntos
Hidrocarbonetos Fluorados/administração & dosagem , Menorragia/tratamento farmacológico , Pirimidinas/administração & dosagem , Animais , Combinação de Medicamentos , Estradiol/administração & dosagem , Feminino , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Humanos , Hidrocarbonetos Fluorados/farmacologia , Leiomioma/complicações , Leiomioma/tratamento farmacológico , Menorragia/etiologia , Noretindrona/administração & dosagem , Pré-Menopausa , Pirimidinas/farmacologia , Neoplasias Uterinas/complicações , Neoplasias Uterinas/tratamento farmacológico
19.
Int J Mol Sci ; 22(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671587

RESUMO

Cell-cell communication is an essential mechanism for the maintenance and development of various organs, including the female reproductive system. Today, it is well-known that the function of the female reproductive system and successful pregnancy are related to appropriate follicular growth, oogenesis, implantation, embryo development, and proper fertilization, dependent on the main regulators of cellular crosstalk, exosomes. During exosome synthesis, selective packaging of different factors into these vesicles happens within the originating cells. Therefore, exosomes contain both genetic and proteomic data that could be applied as biomarkers or therapeutic targets in pregnancy-associated disorders or placental functions. In this context, the present review aims to compile information about the potential exosomes with key molecular cargos that are dysregulated in female reproductive diseases which lead to infertility, including polycystic ovary syndrome (PCOS), premature ovarian failure (POF), Asherman syndrome, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, and preeclampsia, as well as signaling pathways related to the regulation of the reproductive system and pregnancy outcome during these pathological conditions. This review might help us realize the etiology of reproductive dysfunction and improve the early diagnosis and treatment of the related complications.


Assuntos
Biomarcadores/análise , Exossomos , Doenças dos Genitais Femininos/diagnóstico , Doenças dos Genitais Femininos/terapia , Biomarcadores/metabolismo , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/fisiopatologia , Endometriose/diagnóstico , Endometriose/fisiopatologia , Exossomos/fisiologia , Feminino , Doenças dos Genitais Femininos/fisiopatologia , Ginatresia/diagnóstico , Humanos , MicroRNAs , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/fisiopatologia , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/fisiopatologia , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/fisiopatologia , Gravidez , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/fisiopatologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/fisiopatologia
20.
N Engl J Med ; 384(7): 630-642, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33596357

RESUMO

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).


Assuntos
Estradiol/administração & dosagem , Leiomioma/tratamento farmacológico , Menorragia/tratamento farmacológico , Acetato de Noretindrona/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Uterinas/tratamento farmacológico , Adulto , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Estrogênios/administração & dosagem , Feminino , Fogachos/induzido quimicamente , Humanos , Leiomioma/complicações , Menorragia/etiologia , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias Uterinas/complicações , Adulto Jovem
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