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Menopausal women may experience symptoms of depression, sometimes even progressing clinical depression requiring treatment to improve quality of life. While varying levels of estrogen in perimenopause may contribute to an increased biological vulnerability to mood disturbances, the effectiveness of estrogen replacement therapy (ERT) in the relief of depressive symptoms remains controversial. Menopausal depression has a complex, multifactorial etiology, that has limited the identification of optimal treatment strategies for the management of this psychiatric complaint. Nevertheless, clinical evidence increasingly supports the notion that estrogen exerts neuroprotective effects on brain structures related to mood regulation. Indeed, research using preclinical animal models continues to improve our understanding of menopause and the effectiveness of ERT and other substances at treating depression-like behaviors. However, questions regarding the efficacy of ERT in perimenopause have been raised. These questions may be answered by further investigation using specific animal models of reduced ovarian function. This review compares and discusses the advantages and pitfalls of different models emulating the menopausal stages and their relationship with the onset of depressive-like signs, as well as the efficacy and mechanisms of conventional and novel ERTs in treating depressive-like behavior. Ovariectomized young rats, middle-to-old aged intact rats, and females treated with reprotoxics have all been used as models of menopause, with stages ranging from surgical menopause to perimenopause. Additionally, this manuscript discusses the impact of organistic and therapeutic variables that may improve or reduce the antidepressant response of females to ERT. Findings from these models have revealed the complexity of the dynamic changes occurring in brain function during menopausal transition, reinforcing the idea that the best approach is timely intervention considering the opportunity window, in addition to the careful selection of treatment according to the presence or absence of reproductive tissue. Additionally, data from animal models has yielded evidence to support new promising estrogens that could be considered as ERTs with antidepressant properties and actions in endocrine situations in which traditional ERTs are not effective.
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PURPOSE: To analyze the copy number variation (CNV) in the X-linked genes BCORL1, POF1B, and USP9X in idiopathic diminished ovarian reserve (DOR). METHODS: This case-control study included 47 women, 26 with DOR and 21 in the control group. Age, weight, height, BMI, and FSH level were evaluated, as well as antral follicle count (AFC), oocyte retrieval after controlled ovarian stimulation, and metaphase II (MII) oocytes. The CNVs of BCORL1, USP9X, and POF1B genes were measured by quantitative real time PCR (qPCR) using two reference genes, the HPRT1 (X-linked) and MFN2 (autosomal). Protein-protein interaction network and functional enrichment analysis were performed using the STRING database. RESULTS: The mean age was 36.52 ± 4.75 in DOR women and 35.38 ± 4.14 in control. Anthropometric measures did not differ between the DOR and control groups. DOR women presented higher FSH (p = 0.0025) and lower AFC (p < .0001), oocyte retrieval after COS (p = 0.0004), and MII oocytes (p < .0001) when compared to the control group. BCORL1 and POF1B did not differ in copy number between DOR and control. However, DOR women had more copies of USP9X than the control group (p = 0.028). CONCLUSION: The increase in the number of copies of the USP9X gene may lead to overexpression in idiopathic DOR and contribute to altered folliculogenesis and oocyte retrieval.
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Variações do Número de Cópias de DNA , Reserva Ovariana , Ubiquitina Tiolesterase , Humanos , Feminino , Reserva Ovariana/genética , Adulto , Variações do Número de Cópias de DNA/genética , Ubiquitina Tiolesterase/genética , Estudos de Casos e Controles , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/patologia , Recuperação de Oócitos , Proteínas Repressoras/genética , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Oócitos/patologiaRESUMO
BACKGROUND: Helicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been clearly elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes. RESULTS: The results suggested that the deficiency of HFM1 resulting in increased apoptosis and depletion of oocytes in mice, while the oocytes were arrested in the pachytene stage of the first meiotic prophase. In addition, impaired DNA double-strand break repair and disrupted synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by modulating the expression of BRCA1. CONCLUSIONS: These findings elaborated that the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation. This study provided insights into the pathogenesis of POI and highlighted the importance of HFM1 in maintaining proper meiotic function in mouse oocytes.
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Prófase Meiótica I , Oócitos , Ubiquitinação , Animais , Feminino , Camundongos , Apoptose/fisiologia , Quebras de DNA de Cadeia Dupla , Reparo do DNA/fisiologia , Meiose/fisiologia , Prófase Meiótica I/fisiologia , Camundongos Knockout , Oócitos/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteína FUS de Ligação a RNA/genéticaRESUMO
OBJECTIVE: To compare the ovarian reserve of women of reproductive age with and without thyroid autoimmunity (TAI). METHODS: We performed a retrospective analysis of medical records from an assisted reproduction clinic from February 2017 to December 2021. Women aged between18 and 47 years with data on antithyroperoxidase and antithyroglobulin (anti-Tg) antibodies and assessment of ovarian reserve by anti-müllerian hormone (AMH) and antral follicle count (AFC) were included. Among the 188 participants included, 63 were diagnosed with TAI, and 125 had both antibodies negative. AMH and AFC were compared between groups. Subanalysis based on age, types of antibodies, and thyroid function markers were performed. In addition, bivariate analysis and regression models were used. RESULTS: Overall, there was no difference in the median levels of AMH or AFC between the two groups. However, in the subgroup analysis by age, we observed a trend towards lower median levels of AMH in women over 39 years with TAI (0.9 ng/mL vs. 1.5 ng/mL, p=0.08). In a subanalysis according to antibodies, we found a significantly lower median AFC in the group with anti-Tg than in the group without this antibody (8.0 follicles vs. 11.5 follicles, p=0.036). We also found a significantly higher prevalence of anti-Tg in patients with low ovarian reserve compared to those with normal reserve (60.7% vs. 39.3%, p=0.038). CONCLUSIONS: The ovarian reserve of women with TAI appears to be insidiously compromised over the years, with a decreased ovarian reserve in women with anti-Tg.
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Hormônio Antimülleriano , Autoimunidade , Reserva Ovariana , Humanos , Feminino , Reserva Ovariana/fisiologia , Adulto , Estudos Retrospectivos , Hormônio Antimülleriano/sangue , Autoimunidade/fisiologia , Pessoa de Meia-Idade , Adulto Jovem , Autoanticorpos/sangue , Adolescente , Glândula Tireoide/imunologia , Folículo OvarianoRESUMO
OBJECTIVE: Premature ovary failure (POF) is a severe health condition with multiple negative outcomes, which deteriorate a patient's life. The current study aimed to evaluate the therapeutic effect of mesenchymal stem cells (MSCs) derived from peripheral blood in the treatment of women with the POF background. METHODS: The current study was a pilot study carried-out on women younger than 40 with premature ovarian failure. Study participants underwent 4-months cell therapy using Mesenchymal stem cells extracted from peripheral bloods. Serum level of Follicle-stimulating hormone (FSH), Estradiol (E2), Anti-mullerian hormone (AMH), and Antral follicle count (AFC) were the main investigated outcomes that were assessed at baseline, month two and month four of the very small stem cell intervention. RESULTS: Average serum level of FSH was 45.0 (12.1) mIU/mL at baseline and continually decreased during the study and reached 33.2 (12.4) mIU/mL in the fourth month. The average AMH level was 0.10 ng/mL prior to the intervention and increased to 0.13 ng/mL in the 2nd month and 0.15 ng/mL in the fourth month. The level E2 was 85.7 (23.6) pg/ml on average at baseline, while the average E2 reduced to 77.2 (25.6) pg/ml in the fourth month. Average number of AFC was 2.0 (0.8) at baseline. We observed a gradual increase in the second month (Mean AFC=2.2) and after four months it increased to 3.1 (1.8) as the highest menstrual restoration and pregnancy was observed in 10% of our study participants. CONCLUSIONS: MSCs could significantly improve hormone secretion in women with POF. Implantation of MSCs in women with POF background was associated with an increase in AMH and AFC, while it downed the serum level of E2 and FSH. MSCs could also lead to menstrual restoration and pregnancy in women with POF.
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Hormônio Antimülleriano , Hormônio Foliculoestimulante , Transplante de Células-Tronco Mesenquimais , Insuficiência Ovariana Primária , Humanos , Feminino , Insuficiência Ovariana Primária/terapia , Insuficiência Ovariana Primária/sangue , Projetos Piloto , Adulto , Hormônio Antimülleriano/sangue , Hormônio Foliculoestimulante/sangue , Transplante de Células-Tronco Mesenquimais/métodos , Estradiol/sangue , Adulto Jovem , Células-Tronco Mesenquimais/citologiaRESUMO
Objectives: To report the first Mexican case with two novel AARS2 mutations causing primary ovarian failure, uterus infantilis, and early-onset dementia secondary to leukoencephalopathy. Methods: Detailed clinical, clinimetric, neuroimaging features, muscle biopsy with biochemical assays of the main oxidative phosphorylation complexes activities, and molecular studies were performed on samples from a Mexican female. Results: We present a 41-year-old female patient with learning difficulties since childhood and primary amenorrhea who developed severe cognitive, motor, and behavioral impairment in early adulthood. Neuroimaging studies revealed frontal leukoencephalopathy with hypometabolism at the fronto-cerebellar cortex and caudate nucleus. Uterus infantilis was detected on ultrasound study. Clinical exome sequencing identified two novel variants, NM_020745:c.2864G>A (p.W955*) and NM_020745:c.1036C>A (p.P346T, p.P346Wfs*18), in AARS2. Histopathological and biochemical studies on muscle biopsy revealed mitochondrial disorder with cytochrome C oxidase (COX) deficiency. Conclusions: Several adult-onset cases of leukoencephalopathy and ovarian failure associated with AARS2 variants have been reported. To our best knowledge, none of them showed uterus infantilis. Here we enlarge the genetic and phenotypic spectrum of AARS2-related dementia with leukoencephalopathy and ovarian failure and contribute with detailed clinical, clinometric, neuroimaging, and molecular studies to disease and novel molecular variants characterization.
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This study evaluated the protective effect of melatonin before cyclophosphamide administration on ovarian function and its potential mechanism in a mouse model. Two studies were performed. In the first, mice were pretreated with melatonin (10, 20, or 30 mg/kg body weight, i.p.) once daily for 3 days, followed by injection with a single dose of cyclophosphamide (200 mg/kg body weight, i.p.) 30 min after the last melatonin injection. The second study analyzed whether melatonin type 1 and/or 2 receptors mediate the effects of melatonin on the ovary through administration of non-selective MT1/MT2 antagonist (luzindole) or selective MT2 antagonist (4-PPDOT) before the treatment with melatonin plus cyclophosphamide. After treatment groups, the ovaries were harvested and destined to histology, immunohistochemistry, and fluorescence analyses. Lastly, we examined the p-PTEN, p-Akt, and p-FOXO3a participation in the protective effect of melatonin in cyclophosphamide-induced ovarian damage. Results demonstrated that pretreatment with 20 mg/kg melatonin before cyclophosphamide administration showed more morphologically normal follicles, attenuated primordial follicle loss, decreased growing follicle atresia and mitochondrial damage, and increased GSH concentrations. Furthermore, treatment with luzindole blocked the protective effects of melatonin against the damage caused by cyclophosphamide. Additionally, pretreatment with 20 mg/kg melatonin regulated the PTEN/Akt/FOXO3a signaling pathway components after cyclophosphamide treatment. In conclusion, pretreatment with 20 mg/kg melatonin prevented primordial follicle loss and reduced apoptosis and oxidative damage in the mouse ovary during experimental chemotherapy with cyclophosphamide. Furthermore, the MT1 receptor and PTEN/Akt/FOXO3a proteins mediated these cytoprotective effects.
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Melatonina , Animais , Peso Corporal , Ciclofosfamida/farmacologia , Feminino , Melatonina/farmacologia , Camundongos , Ovário/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
BACKGROUND: Graft-versus-host disease (GVHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD in the female genital tract can cause sinusorrhagia, dyspareunia, synechia, and even complete vagina occlusion. PURPOSE: This prospective study aimed to evaluate the clinical characteristics and effects of preventive and prompt treatment for genital GVHD in females undergoing HSCT (n = 40). RESULTS: Genital GVHD was diagnosed in 11 of 40 patients (27.5%), and the most common complaint was vaginal dryness (54.6%). The majority of patients (63.6%) presented mild genital GVHD (clinical score 1), with interlabial fissures and lichen-like lesions, while a minority of patients (9.1%) presented advanced genital GVHD (clinical score 3) with the fusion of the small and large lips. The median time of onset of genital GVHD signs was 10 months after HSCT, concomitant with GVHD in the skin and oral cavity. Personalized and topical therapy was effective in most cases (81.8%), and no patient required surgical intervention. CONCLUSION: We confirmed that female genital GVHD affects approximately one-third of females undergoing HSCT, highlighting the importance of periodic gynecological monitoring for early detection and treatment to improve care for these females.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doenças Vaginais , Feminino , Genitália Feminina/patologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Prospectivos , Doenças Vaginais/diagnóstico , Doenças Vaginais/etiologia , Doenças Vaginais/terapiaRESUMO
Coats plus syndrome is an autosomal recessive multisystemic and pleiotropic disorder affecting the eyes, brain, bone, and gastrointestinal tract, usually caused by compound heterozygous variants of the conserved telomere maintenance component 1 gene (CTC1), involved in telomere homeostasis and replication. So far, most reported patients are compound heterozygous for a truncating mutation and a missense variant. The phenotype is believed to result from telomere dysfunction, with accumulation of DNA damage, cellular senescence, and stem cell depletion. Here, we report a 23-year-old female with prenatal and postnatal growth retardation, microcephaly, osteopenia, recurrent fractures, intracranial calcification, leukodystrophy, parenchymal brain cysts, bicuspid aortic valve, and primary ovarian failure. She carries a previously reported maternally inherited pathogenic variant in exon 5 (c.724_727del, p.(Lys242Leufs*41)) and a novel, paternally inherited splice site variant (c.1617+5G>T; p.(Lys480Asnfs*17)) in intron 9. CTC1 transcript analysis showed that the latter resulted in skipping of exon 9. A trace of transcripts was normally spliced resulting in the presence of a low level of wild-type CTC1 transcripts. We speculate that ovarian failure is caused by telomere shortening or chromosome cohesion failure in oocytes and granulosa cells, with early decrease in follicular reserve. This is the first patient carrying 2 truncating CTC1 variants and the first presenting primary ovarian failure.
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Calcinose , Cistos do Sistema Nervoso Central , Leucoencefalopatias , Ataxia/genética , Ataxia/patologia , Neoplasias Encefálicas , Calcinose/genética , Cistos do Sistema Nervoso Central/genética , Cistos do Sistema Nervoso Central/patologia , Feminino , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Espasticidade Muscular , Mutação , Doenças Retinianas , Convulsões , Proteínas de Ligação a Telômeros/genéticaRESUMO
Resumen: el síndrome X frágil es la causa más frecuente de retraso psicomotor vinculado al cromosoma X en niños, con una prevalencia de 1 : 5.000 en hombres y 1 : 4.000 - 8.000 en mujeres. Además, es la causa hereditaria más asociada al síndrome del espectro autista. Esta patología posee como base etiológica la expansión del triplete CGG en el extremo distal del gen FMR1, lo que causa su silenciamiento. Los pacientes afectados con este síndrome suelen padecer de problemas conductuales, neurológicos, cardíacos y ortopédicos. Este síndrome también se relaciona con la insuficiencia ovárica primaria asociada al X frágil, y el síndrome de temblor y ataxia asociado al X frágil que afectan a la madre y al abuelo materno, y que, por su reciente descripción, podrían ser desconocidos por el personal sanitario, lo que retrasa su diagnóstico y tratamiento. El objetivo de este artículo es analizar estas enfermedades, con el fin de describir el conocimiento actual sobre su etiología, las manifestaciones clínicas, el diagnóstico y el tratamiento. Esto se realizó mediante la recopilación de artículos en Pubmed, con algunas contribuciones de las bases de datos Scielo, Redalyc, Europe PMC, Science Direct, Google Académico y Genetics Home Reference. Entre las conclusiones principales se destaca que los fenotipos asociados a la premutación del gen FMR1 contemplan mecanismos fisiopatológicos diferentes al síndrome X frágil, a pesar de estar íntimamente relacionados.
Abstract: fragile X syndrome is the most common cause of X-linked psychomotor retardation in children, with a prevalence of 1 : 5.000 in males and 1 : 4.000 -8.000 in females. It is also the hereditary cause most associated with autism spectrum syndrome. The etiological basis of this pathology is the expansion of the CGG triplet at the distal end of the FMR1 gene, which causes its silencing. Patients affected with this syndrome usually suffer from behavioral, neurological, cardiac and orthopedic problems. This syndrome is also related to Fragile X-associated primary ovarian insufficiency, and Fragile X-associated tremor and ataxia syndrome affecting the mother and maternal grandfather, which, because of their recent description, may be unknown to health care providers, delaying their diagnosis and treatment. The objective of this article is to analyze these diseases, in order to describe the current knowledge about their etiology, clinical manifestations, diagnosis and treatment. This was done by collecting articles in Pubmed, with some contributions from Scielo, Redalyc, Europe PMC, Science Direct, Google Scholar and Genetics Home Reference databases. Among the main conclusions, it is highlighted that the phenotypes associated with FMR1 gene premutation involve different pathophysiological mechanisms to Fragile X syndrome, despite being closely related.
Resumo: a síndrome do X frágil é a causa mais comum de retardo psicomotor ligado ao cromossomo X em crianças, com prevalência de 1 : 5.000 em homens e 1 : 4.000 a 8.000 em mulheres. Além disso, é a causa mais hereditária associada à síndrome do espectro do autismo. Essa patologia tem como base etiológica a expansão do trigêmeo CGG na extremidade distal do gene FMR1, o que causa seu silenciamento. Pacientes com essa síndrome geralmente sofrem de problemas comportamentais, neurológicos, cardíacos e ortopédicos. Essa síndrome também está relacionada à insuficiência ovariana primária associada ao X frágil, à síndrome do tremor e à ataxia associada ao X frágil, que acometem a mãe e o avô materno, e que, devido à sua descrição recente, poderiam ser desconhecidas pelos profissionais de saúde, o que atrasa seu diagnóstico e tratamento. O objetivo deste artigo é analisar essas doenças, a fim de descrever o conhecimento atual sobre sua etiologia, manifestações clínicas, diagnóstico e tratamento. Isso foi feito através da recopilação de artigos no Pubmed, com algumas contribuições das bases de dados Scielo, Redalyc, Europe PMC, Science Direct, Google Academic e Genetics Home Reference. Dentre as principais conclusões, destaca-se que os fenotipos associados à premutação do gene FMR1 incluem outros mecanismos fisiopatológicos além da síndrome do X frágil, apesar de eles estarem intimamente relacionados.
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El objetivo de este manuscrito es realizar una revisión y actualización de la literatura de la insuficiencia ovárica primaria (IOP) en población adolescente, a partir del diagnóstico, manejo y seguimiento de un caso clínico. La insuficiencia ovárica primaria se define como la menopausia en una mujer antes de los 40 años, acompañada de amenorrea, hipogonadismo hipergonadotrópico e infertilidad. Su prevalencia varía entre 1 a 2%, y en mujeres menores de 20 años su prevalencia es un caso de cada 10,000. Aunque se sabe que muchas afecciones pueden llevar a una IOP, la más común es la causa idiopática. La presentación clínica es diversa, y varios trastornos diferentes pueden también, llevar a esta condición. CASO CLÍNICO: Se presenta el caso de una adolescente de 17 años, previamente sana, con historia de amenorrea secundaria, no embarazada, con examen físico general y ginecológico normal. Se solicita estudio analítico complementario resultando con niveles de hormona folículo estimulante (FHS), estradiol (E2) y hormona antimülleriana (AMH) compatibles con una insuficiencia ovárica como la observada en la posmenopausia. Se inicia terapia hormonal (TH) clásica con estradiol y progesterona, siendo posteriormente reemplazada por anticoncepción hormonal combinada (AHC) oral, coincidente con el inicio de vida sexual, con respuesta favorable y sangrados regulares. La IOP tiene graves consecuencias para la salud incluyendo trastornos psicológicos como angustia, síntomas depresivos o depresión, infertilidad, osteoporosis, trastornos autoinmunes, cardiopatía isquémica, y un mayor riesgo de mortalidad. La enfermedad de Hashimoto es el trastorno autoinmune más frecuente asociado a la IOP. Su tratamiento y diagnóstico deben establecerse de forma precoz para evitar consecuencias a largo plazo. La terapia con estrógenos es la base del tratamiento para eliminar los síntomas de la deficiencia de estrógenos, además de evitar las consecuencias futuras del hipogonadismo no tratado. También el manejo debe incluir los siguientes dominios: fertilidad y anticoncepción, salud ósea, problemas cardiovasculares, función psicosexual, psicológica y neurológica, informando a los familiares y a la paciente sobre la dimensión real de la IOP y la necesidad de tratamiento multidisciplinario en muchos casos. CONCLUSIÓN: El caso presentado, pese a ser infrecuente, permite abordar de manera sistematizada el diagnostico de IOP y evaluar alternativas de manejo plausibles para evitar graves consecuencias en la salud, así como conocer respuesta clínica y de satisfacción de la adolescente.
The objective of this manuscript is to review and update the literature on primary ovarian insufficiency (POI) in an adolescent population, based on the diagnosis, management and follow-up of a clinical case. Primary ovarian insufficiency is defined as menopause in a woman before the age of 40, accompanied by amenorrhea, hypergonadotropic hypogonadism, and infertility. Its prevalence varies between 1 to 2%, and in women under 20 years of age its prevalence is one case in every 10,000. Although it is known that many conditions can lead to POI, the most common is the idiopathic cause. The clinical presentation is diverse, and several different disorders can also lead to this condition. CLINICAL CASE: The case of a 17-year-old adolescent, previously healthy, with a history of secondary amenorrhea, not pregnant, with a normal general physical and gynecological examination is presented. A complementary analytical study is requested, resulting in levels of follicle stimulating hormone (FHS), estradiol (E2) and anti-müllerian hormone (AMH) compatible with ovarian insufficiency such as that observed in postmenopause. Classic hormonal therapy (HT) with estradiol and progesterone was started, later being replaced by combined hormonal contraception (CHC), coinciding with the beginning of sexual life, with a favorable response and regular bleeding. POI has serious health consequences including psychological disorders such as distress, depressive symptoms or depression, infertility, osteoporosis, autoimmune disorders, ischemic heart disease, and an increased risk of mortality. Hashimoto's disease is the most common autoimmune disorder associated with POI. Its treatment and diagnosis must be established early to avoid long-term consequences. Estrogen therapy is the mainstay of treatment to eliminate the symptoms of estrogen deficiency, in addition to avoiding the future consequences of untreated hypogonadism. Management should also include the following domains: fertility and contraception, bone health, cardiovascular problems, psychosexual, psychological and neurological function, informing family members and the patient about the real dimension of POI and the need for multidisciplinary treatment in many cases. CONCLUSION: The case, although infrequent, allows a systematic approach to the diagnosis of POI and evaluate plausible management alternatives to avoid serious health consequences, as well as to know the clinical response and satisfaction of the adolescent.
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Humanos , Feminino , Gravidez , Adolescente , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/tratamento farmacológico , Menopausa Precoce , Terapia de Reposição Hormonal , Estradiol/análise , Hormônio Antimülleriano/análise , Amenorreia/etiologia , Hormônio Foliculoestimulante/análise , Infertilidade FemininaRESUMO
Drug-Free IVA has been recently introduced as a therapeutic option for patients with Primary Ovarian Insufficiency (POI). Despite the existing limited results, it can be considered as a promising option for these patients to achieve their own offspring. Here we report the case of a 35-year-old woman diagnosed with POI at 30 years of age. Drug-Free IVA was performed at age 33 and pregnancy was achieved by IVF 10 months after grafting. Unfortunately, she had a preterm delivery with neonatal death due to prematurity complications. After delivery, she recovered spontaneous ovarian function and one mature oocyte was retrieved 20 months after Drug-Free IVA. Following IVF, one embryo was transferred, and she is currently 33 weeks pregnant, suggesting that Drug-free IVA could lead to long-term ovarian function.
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Insuficiência Ovariana Primária , Adulto , Feminino , Fertilização in vitro , Humanos , GravidezRESUMO
In the present case series our aim is to present seven patients with extremely decreased ovarian reserve and oligomenorrhea, conceived with in vitro fertilization following a very short ovarian stimulation of incidentally detected big antral follicles. The study included women pursuing in vitro fertilization due to premature ovarian failure risk. When an incidental growing antral follicle was detected under ultrasound, immediate ovarian stimulation was initiated if the blood estradiol, luteinizing hormone and progesterone levels were correlated. Serum anti-Mullerian hormone measurements of all patients were consistent with extremely diminished ovarian reserve (ranged between 0.01 and 0.09ng/ml) and FSH levels varied between 13-104IU/l. The mean stimulation length ranged between 2-4 days. A total of 8 oocytes were retrieved; 6 MII, 1 GV and 1 degenerated. All 6 MII oocytes were fertilized with intracytoplasmic sperm injection. Two patients conceived after fresh embryo transfer, whereas the one conceived following frozen thawed embryo transfer. The ongoing pregnancy rate was 50% per transfer, and two of them resulted in a healthy live birth. In conclusion, close monitoring of oligoamenorrheic infertile patients who are at high risk of imminent ovarian failure using ultrasound and blood hormone levels is very important. Albeit low, the possibility of having a healthy pregnancy following "a very short ovarian stimulation" in such a specific patient group is emphasized.
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Reserva Ovariana , Feminino , Fertilização in vitro , Humanos , Nascido Vivo , Folículo Ovariano/diagnóstico por imagem , Indução da Ovulação , Gravidez , Injeções de Esperma IntracitoplásmicasRESUMO
CONTEXT: Follicle-stimulating hormone (FSH) plays an essential role in gonadal function. Loss-of-function mutations in the follicle-stimulating hormone receptor (FSHR) are an infrequent cause of primary ovarian failure. OBJECTIVE: To analyze the molecular physiopathogenesis of a novel mutation in the FSHR identified in a woman with primary ovarian failure, employing in vitro and in silico approaches, and to compare the features of this dysfunctional receptor with those shown by the trafficking-defective D408Y FSHR mutant. METHODS: Sanger sequencing of the FSHR cDNA was applied to identify the novel mutation. FSH-stimulated cyclic adenosine monophosphate (cAMP) production, ERK1/2 phosphorylation, and desensitization were tested in HEK293 cells. Receptor expression was analyzed by immunoblotting, receptor-binding assays, and flow cytometry. Molecular dynamics simulations were performed to determine the in silico behavior of the mutant FSHRs. RESULTS: A novel missense mutation (I423T) in the second transmembrane domain of the FSHR was identified in a woman with normal pubertal development but primary amenorrhea. The I423T mutation slightly impaired plasma membrane expression of the mature form of the receptor and severely impacted on cAMP/protein kinase A signaling but much less on ß-arrestin-dependent ERK1/2 phosphorylation. Meanwhile, the D408Y mutation severely affected membrane expression, with most of the FSH receptor located intracellularly, and both signal readouts tested. Molecular dynamics simulations revealed important functional disruptions in both mutant FSHRs, mainly the loss of interhelical connectivity in the D408Y FSHR. CONCLUSIONS: Concurrently, these data indicate that conformational differences during the inactive and active states account for the distinct expression levels, differential signaling, and phenotypic expression of the I423T and D408Y mutant FSHRs.
Assuntos
Insuficiência Ovariana Primária/genética , Receptores do FSH/genética , Adulto , Amenorreia/genética , Amenorreia/metabolismo , Substituição de Aminoácidos , Família , Feminino , Hormônio Foliculoestimulante/farmacologia , Células HEK293 , Humanos , Isoleucina/genética , Mutação com Perda de Função/genética , Modelos Moleculares , Mutação de Sentido Incorreto , Linhagem , Insuficiência Ovariana Primária/metabolismo , Receptores do FSH/agonistas , Receptores do FSH/química , Receptores do FSH/metabolismo , Treonina/genéticaRESUMO
The present study evaluated the effects of protocatechuic acid (PCA) after cisplatin-induced ovarian toxicity in mice and if PTEN and FOXO3a proteins are involved in PCA action. The mice were divided into five experimental groups (five animals per group) and treated once a day for 3 days as follows: (1) the control group was pretreated with oral administration (o.p.) of saline solution, followed by an intraperitoneal (i.p.) injection of saline solution. The other groups were pretreated (o.p.) with (2) saline solution (cisplatin group), (3) N-acetylcysteine (150 mg/kg of body weight), or with (4) 20 or (5) 50 mg/kg body weight of PCA, followed by 5 mg/kg body weight (i.p.) of cisplatin. Next, the ovaries were destined to histological (morphology and activation), immunohistochemical (PCNA and cleaved caspase-3 expression), and fluorescence (reactive oxygen species [ROS], glutathione [GSH], and active mitochondria levels) analyses. Moreover, the immunoreactivity for p-PTEN and p-FOXO3a was evaluated to investigate a potential mechanism by which PCA could prevent the cisplatin-induced ovarian damage. Pretreatment with N-acetylcysteine or 20 mg/kg PCA before cisplatin preserved the percentage of normal follicles and cell proliferation as observed in the control, reduced apoptosis and ROS levels, and showed higher active mitochondria and GSH levels than the cisplatin treatment (P < 0.05). Moreover, pretreatment with 20 mg/kg PCA decreased cisplatin-induced p-PTEN and increased (P < 0.05) nuclear export of p-FOXO3a. In conclusion, PCA at 20 mg/kg reduced apoptosis, maintained cell proliferation and mitochondrial function, reduced ROS production, and increased GSH expression likely through the involvement of PTEN and FOXO3a proteins.
Assuntos
Proteína Forkhead Box O3/metabolismo , Hidroxibenzoatos/farmacologia , Doenças Ovarianas/prevenção & controle , Ovário/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Ovarianas/induzido quimicamente , Doenças Ovarianas/enzimologia , Doenças Ovarianas/patologia , Ovário/metabolismo , Ovário/patologia , Fosforilação , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVE: To evaluate anxiety, depression and stress of POI women using hormone therapy. METHODS: A quantitative cross-sectional study included 61 women diagnosed with POI receiving HT, and 61 women with preserved ovarian function, matched 1:1 for age (control group). Instruments used to evaluate depression, anxiety and stress were Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Lipp's Stress Symptom Inventory (LSSI). The chi-square or Fisher's exact tests, Mann-Whitney test, Spearman's correlation coefficient or logistic regression analysis with stepwise criteria were used for analysis. RESULTS: The mean age of POI women and control group was 35.03±7.68 and 34.49±7.55 years old (p = 0.63). POI group and control group had a mean of 0.44±0.92 and 1.28±1.38 children (p = 0,001); the total BDI, BAI and LSSI scores were 15.72±11.68 and 13.66±8.44 (p = 0.64); 17.54±13.16 and 17.25±11.05 (p = 0.90), 19.39±12.08 and 18.93±11.21 (p = 0.945). The majority of women did not have depression or presented mild depression, but approximately one-third had moderate-severe undiagnosed depressive or anxiety symptoms. In POI group, depression was positively correlated with the number of children and anxiety. Anxiety and stress were also positively correlated. It was observed that for each point in the BDI, the risk of stress above 20 increased 19.6%, while for each point in the BAI, the risk of greater stress increased 32.4%. LIMITATIONS: This is a cross-sectional study, which made it impossible to draw cause and effect conclusions CONCLUSION: Women with POI receiving HT have indexes of depression, anxiety and stress similar to the population of women with preserved ovarian function.
Assuntos
Insuficiência Ovariana Primária , Adulto , Ansiedade/epidemiologia , Criança , Estudos Transversais , Depressão/epidemiologia , Feminino , Hormônios , HumanosRESUMO
La función ovárica depende de la expresión de múltiples genes, por lo que las anomalías del cromosoma X y los autosomas revisten gran importancia en la etiología de la insuficiencia ovárica primaria (IOP). Las translocaciones de autosomas en mujeres con IOP son muy raras y solo se han detectado tres casos: dos translocaciones entre los cromosomas 2 y 15 en dos mujeres con cariotipo 46, XX, t (2, 15) (q32.3, q13.3)2; una translocación entre los cromosomas 13 y 14 en una mujer con cariotipo 45, XX, t (13; 14)3; por lo que nuestro caso sería el cuarto reporte de mujeres con translocaciones de autosomas e IOP.
Ovarian function depends on the expression of multiple genes, so Xchromosome abnormalities and autosomes are of great importance in the etiology of primary ovarian insufficiency (IOP). Autosomal translocations in women with IOP are very rare and only three cases have been detected: two translocations between chromosomes 2 and 15 in two women with karyotype 46, XX, t (2, 15) (q32.3, q13.3)2; a translocation between chromosomes 13 and 14 in a woman with karyotype 45, XX, t (13; 14)3 , so our case would be the fourth report of women with autosomal translocations and IOP.
Assuntos
Humanos , Feminino , Adulto , Aberrações Cromossômicas , Insuficiência Ovariana Primária/genética , Amenorreia/genética , Translocação Genética , CariótipoRESUMO
The classical definition of hypogonadism, used in adult medicine, as gonadal failure resulting in deficient steroid and gamete production, and its classification into hypergonadotropic and hypogonadotropic refer to primary gonadal and hypothalamic-pituitary disorders respectively and may lead to under- or misdiagnosis in pediatrics. Indeed, in children with primary gonadal failure, gonadotropin levels may be within the reference range for age. Conversely, since gonadotropins and steroids are normally low during childhood, it may prove impossible to show the existence of a hypogonadotropic state before pubertal age. Anti-Müllerian hormone (AMH) and inhibin B arise as more adequate biomarkers to assess gonadal function and increase the possibility of making an earlier diagnosis of hypogonadism in children, which may positively impact on timely management.
Assuntos
Genitália/fisiopatologia , Hipogonadismo/fisiopatologia , Androgênios/sangue , Hormônio Antimülleriano/sangue , Feminino , Genitália/metabolismo , Gonadotropinas/sangue , Humanos , Hipogonadismo/sangue , Masculino , Pediatria/métodos , Gravidez , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/fisiopatologia , Testosterona/sangueRESUMO
About 10% of women of reproductive age are unable to conceive or carry a pregnancy to term. Female factors alone account for at least 35% of all infertility cases and comprise a wide range of causes affecting ovarian development, maturation of oocytes, and fertilization competence, as well as the potential of a fertilized egg for preimplantation development, implantation, and fetal growth. Genetic abnormalities leading to infertility in females comprise large chromosome abnormalities, submicroscopic chromosome deletion and duplications, and DNA sequence variations in the genes that control numerous biological processes implicated in oogenesis, maintenance of ovarian reserve, hormonal signaling, and anatomical and functional development of female reproductive organs. Despite the great number of genes implicated in reproductive physiology by the study of animal models, only a subset of these genes is associated with human infertility. In this review, we mainly focus on genetic alterations identified in humans and summarize recent knowledge on the molecular pathways of oocyte development and maturation, the crucial role of maternal-effect factors during embryogenesis, and genetic conditions associated with ovarian dysgenesis, primary ovarian insufficiency, early embryonic lethality, and infertility.
Assuntos
Infertilidade Feminina/genética , Oogênese/genética , Animais , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Feminino , Humanos , Relações Materno-Fetais/fisiologia , Reserva Ovariana/genética , Gravidez , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/genética , Reprodução/genética , Transdução de Sinais/genéticaRESUMO
CASE PRESENTATION: a 35 year-old physical educator sought gynecological care for secondary amenorrhea and infertility. She denied the occurrence of similar problems in her family and referred to hypothyroidism as her only comorbidity, for which she was on levothyroxine 88µg daily. She was tested for beta-HCG, prolactin and TSH levels. She was negative for beta-HCG, and had prolactin and TSH levels of 19ng/ml and 2.04 mIU/ml, respectively. Her progesterone test was negative. The combined test (estradiol + norethisterone acetate) was positive, excluding the possibility of an anatomical cause. One month later, her blood tests were as follows: FSH 100mIU/ml, TSH 1.54mIU/ml, free T4 1.22ng/dl, and anti-TPO 261U/ml. Her FSH level was above 100 and she was diagnosed with premature ovarian failure. Reproductive treatment with donor eggs was proposed as an option. Karyotyping and a test for fragile X syndrome were ordered. A few months later the patient came to our clinic saying she was having menstrual cycles. Blood tests were as follows: FSH 9.2mIU/ml; TSH 2.21mIU/ml; and anti-TPO 14U/ml. Transvaginal ultrasound showed a normal uterus with a thin endometrium and atrophic ovaries. After two years of irregular menstrual cycles, she became amenorrheic again. She chose not to undergo assisted reproduction. This paper discusses the diagnosis of premature ovarian failure in light of current protocols and the association of this condition with diseases such as Hashimoto's thyroiditis, and looks into the difficulty of performing differential diagnosis against Savage syndrome and of offering reproductive counseling especially in cases where the menstrual cycle returns.