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1.
Maturitas ; 131: 78-86, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31787151

RESUMO

Ovarian deficiency, including diminished ovarian reserve and premature ovarian insufficiency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insufficiency often has a genetic basis, with genes affecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26-8% of patients with premature ovarian insufficiency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an in-depth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insufficiency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insufficiency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance.


Assuntos
Infertilidade Feminina/genética , Menopausa Precoce/genética , Reserva Ovariana , Insuficiência Ovariana Primária/genética , Fator Esteroidogênico 1/genética , Adulto , Grupo com Ancestrais do Continente Africano , Alelos , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Infertilidade Feminina/etnologia , Menopausa Precoce/etnologia , Mutação , Insuficiência Ovariana Primária/etnologia
3.
Exp Suppl ; 111: 367-383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588540

RESUMO

Nowadays, women's family planning intentions are postponed, and it is common that only later will the conditions be created for the woman to have children. Fortunately, in most cases, pregnancy is possible in this case, taking into account the increased genetic risk. However, this later childbirth may become impossible or significantly more difficult if we can detect sterility and infertility, and its genetic cause is revealed. Any procedure that can help to reduce the "aging" of society, the reproduction rate, must be treated as an important public health issue. It would be particularly important in cases where genetic causes can be detected in the background of female sterility and infertility. Endocrine causes, infections, immunological causes, psychic factors, stress, and weight problems may be among the causes of female infertility in addition to genetic causes and genetic developmental disorders. Infertility can also be caused by iatrogenic factors, previous interventions, and surgery. In this chapter we will discuss the diseases in which genetic factors play a role.


Assuntos
Infertilidade Feminina/genética , Feminino , Humanos , Gravidez
4.
J Assist Reprod Genet ; 36(9): 1957-1962, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31428887

RESUMO

PURPOSE: To identify the disease-causing gene in a family with female infertility and fertilization failure. METHODS: Whole-exome sequencing and Sanger sequencing were used to identify the disease-causing gene in a female with infertility and fertilization failure. Subcellular localization and western blot analysis were used to check the effect of mutations. RESULTS: We identified novel compound heterozygous mutations c.598C>T (p.Arg200Ter) and c.1319G>C (p.Trp440Ser) in WEE2 gene in a female with infertility and fertilization failure. The p.Arg200Ter mutant WEE2 gene produce truncated protein and mainly located in the nucleus, the same as the wild protein, while the p.Trp440Ser mutant WEE2 proteins are located in the nucleus and cytoplasm and the expression level of p.Trp440Ser mutant WEE2 protein is reduced significantly compared with that of wild-type WEE2. CONCLUSIONS: We discovered novel compound heterozygous mutations c.598C>T (p.Arg200Ter) and c.1319G>C (p.Trp440Ser) in WEE2 gene in a female whose oocytes could not form pronucleus after intracytoplasmic sperm injection (ICSI). Moreover, mutations in WEE2 gene affect the normal function of WEE2 proteins and cause fertilization failure.


Assuntos
Proteínas de Ciclo Celular/genética , Infertilidade Feminina/genética , Proteínas Tirosina Quinases/genética , Adulto , Proteínas de Ciclo Celular/metabolismo , Feminino , Expressão Gênica , Células HEK293 , Células HeLa , Heterozigoto , Humanos , Infertilidade Feminina/patologia , Masculino , Mutação , Oócitos/patologia , Proteínas Tirosina Quinases/metabolismo , Injeções de Esperma Intracitoplásmicas , Falha de Tratamento , Sequenciamento Completo do Exoma
5.
Andrologia ; 51(9): e13370, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31332817

RESUMO

Kisspeptin, a peptide hormone, plays a pivotal role in fertility and neuroendocrine regulation of hypothalamo-pituitary-gonadal axis. Increased kisspeptin and reproductive hormones are responsible for fertility in male and females. This study aimed to explore the role of kisspeptin on hypothalamo-pituitary-gonadal axis by comparing the levels of kisspeptin in fertile and infertile subjects and identifying single nucleotide polymorphisms (SNPs) of KISS1 gene in exon 2 and exon 3 of infertile male and female cohorts. A cross-sectional study was carried out on 80 males (44 infertile and 36 fertile) and 88 females (44 in each group). Significantly high levels of kisspeptin (KP), follicle-stimulating hormone (FSH), luteinizing hormone and testosterone were observed in fertile male and female subjects except low FSH levels in comparison with infertile female subjects. One polymorphism in exon 2 (E1225K [G/A 3673]) and three in exon 3 (P1945A [C/G 5833]; Insertion of T at 6075; G2026G [C/G 6078]) in infertile group were detected, with low KP and hormonal levels. Male subjects had abnormal sperm parameters and unsuccessful attempt of intracytoplasmic sperm injection in females. Expression of SNP in exon 2 and exon 3 of KISS1 could be responsible for alteration in release of reproductive hormones and gonadal functions, hence causing infertility.


Assuntos
Sistema Hipotálamo-Hipofisário/fisiopatologia , Infertilidade Feminina/genética , Infertilidade Masculina/genética , Kisspeptinas/genética , Adulto , Estudos Transversais , Éxons/genética , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/epidemiologia , Infertilidade Masculina/sangue , Infertilidade Masculina/epidemiologia , Kisspeptinas/sangue , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Paquistão/epidemiologia , Polimorfismo de Nucleotídeo Único , Testosterona/sangue
6.
Nat Commun ; 10(1): 3086, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300655

RESUMO

Mammalian fertilisation begins when sperm interacts with the egg zona pellucida (ZP), whose ZP1 subunit is important for fertility by covalently cross-linking ZP filaments into a three-dimensional matrix. Like ZP4, a structurally-related component absent in the mouse, ZP1 is predicted to contain an N-terminal ZP-N domain of unknown function. Here we report a characterisation of ZP1 proteins carrying mutations from infertile patients, which suggests that, in human, filament cross-linking by ZP1 is crucial to form a stable ZP. We map the function of ZP1 to its ZP-N1 domain and determine crystal structures of ZP-N1 homodimers from a chicken homolog of ZP1. These reveal that ZP filament cross-linking is highly plastic and can be modulated by ZP1 fucosylation and, potentially, zinc sparks. Moreover, we show that ZP4 ZP-N1 forms non-covalent homodimers in chicken but not in human. Together, these data identify human ZP1 cross-links as a promising target for non-hormonal contraception.


Assuntos
Infertilidade Feminina/genética , Domínios Proteicos/fisiologia , Glicoproteínas da Zona Pelúcida/metabolismo , Zona Pelúcida/metabolismo , Animais , Galinhas , Cristalografia por Raios X , Feminino , Fertilização/fisiologia , Mutação da Fase de Leitura , Humanos , Simulação de Dinâmica Molecular , Multimerização Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura , Alinhamento de Sequência , Glicoproteínas da Zona Pelúcida/genética , Glicoproteínas da Zona Pelúcida/isolamento & purificação , Glicoproteínas da Zona Pelúcida/ultraestrutura
7.
J Biol Regul Homeost Agents ; 33(3): 883-887, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31184100

RESUMO

Glycoprotein Ia (GPIa), also known as integrin alpha 2 (ITGA2), together with GPIIa (ITGB1), form the heterodimer integrin α2ß1. This complex is a major collagen receptor on the membrane of platelets, which is involved in thrombus formation through platelet adhesion and activation.


Assuntos
Fertilização In Vitro , Infertilidade Feminina/genética , Integrina alfa2/genética , Plaquetas , Feminino , Humanos , Polimorfismo Genético , Falha de Tratamento
8.
Int J Mol Med ; 44(2): 375-389, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173155

RESUMO

Telomere length (TL) has long been associated with aging, as telomeres serve as protective caps of chromosomes, and are thus deeply involved in the preservation of genome integrity and are vital to cellular functions. Traditionally, a strong link connects aging and infertility in both sexes, with an earlier onset in females. Over the past decade, telomeres have attracted increasing attention due to the role they play in fertility. In this review, we investigated the potential positive or negative association between relative TL and different factors of female and male infertility. A systematic search of the PubMed database was conducted. Out of the 206 studies identified, 45 were reviewed as they fulfilled the criteria of validity and relevance. Following an analysis and a comparison of the study outcomes, several clear trends were observed. The majority of female infertility factors were associated with a shorter TL, with the exception of endometriosis, premature ovarian failure and clear cell carcinoma that were associated with a longer TL and polycystic ovary syndrome (PCOS), which revealed conflicting results among several studies, leading to ambiguous conclusions. Male infertility factors were associated with a shorter TL. Although this review can provide an outline of general trends in the association of TL with infertility factors, further epidemiological and original research studies are required to focus on investigating the basis of these varying lengths of telomeres.


Assuntos
Infertilidade Feminina/genética , Infertilidade Masculina/genética , Encurtamento do Telômero , Envelhecimento , Feminino , Humanos , Infertilidade Feminina/etiologia , Infertilidade Feminina/patologia , Infertilidade Masculina/etiologia , Infertilidade Masculina/patologia , Masculino , Telômero/genética
9.
J Assist Reprod Genet ; 36(6): 1143-1152, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31115740

RESUMO

PURPOSE: To investigate whether unexplained infertility at a young age demonstrates manifestations of decreased ovarian reserve. METHODS: A total of 100 women were divided into two equally sized groups. The study group comprised women aged ≤ 37 years diagnosed with unexplained infertility, and the control group included age-matched women with either mechanical factor or severe male factor infertility. RESULTS: Both groups were comparable in their basic characteristics. Overall, women with unexplained infertility presented with inferior ovarian reserve results set against women of the control group. The number of ≥ 14-mm follicles on the day of hCG administration was significantly lower in the study compared with the control group (7.0 ± 4.5 vs. 10.4 ± 4.1 follicles, respectively, P < 0.001). Likewise, basal serum FSH was higher in the study compared with the control group (8.4 ± 5.5 vs. 6.4 ± 1.7 IU/L, respectively, P = 0.015), while antral follicle count was lower (10.9 ± 6.6 vs. 16.2 ± 6.6 follicles, respectively, P < 0.001). Furthermore, women with unexplained infertility required a higher total dose of FSH for ovarian stimulation (2,923 ± 1,701 vs. 2,196 ± 941 IU/L, respectively, P = 0.010), but exhibited a lower number of retrieved oocytes (9.3 ± 6.3 vs. 15.6 ± 7.9 oocytes, respectively, P < 0.001), alongside a lower number of achieved embryos (5.3 ± 4.0 vs. 8.0 ± 4.7 embryos, respectively, P = 0.002). Interestingly, the cumulative clinical pregnancy rate was not significantly different between the two groups (44% vs. 58%, respectively, P = 0.163). CONCLUSIONS: Young women ≤ 37 years of age with unexplained infertility have clear manifestations of sub-optimal ovarian reserve set against controls. Our findings suggest that unexplained infertility at a young age may be a risk factor for developing poor ovarian response, specifically as a quantitative, rather than a qualitative, risk factor.


Assuntos
Infertilidade Feminina/diagnóstico , Doenças Ovarianas/genética , Reserva Ovariana/fisiologia , Adulto , Transferência Embrionária , Feminino , Fertilização In Vitro , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/fisiopatologia , Recuperação de Oócitos , Doenças Ovarianas/diagnóstico , Doenças Ovarianas/fisiopatologia , Indução da Ovulação/métodos , Gravidez , Taxa de Gravidez , Injeções de Esperma Intracitoplásmicas , Adulto Jovem
10.
Genes (Basel) ; 10(6)2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31142036

RESUMO

Host immunogenetic factors can affect late complications of urogenital infections with Chlamydia trachomatis. These findings are creating new avenues for updating existing risk prediction models for C. trachomatis-associated tubal factor infertility (TFI). Research into host factors and its utilization may therefore have future implications for diagnosing C. trachomatis-induced infertility. We outline the epidemiological situation regarding C. trachomatis and TFI in high-income countries. Thereupon, we review the main characteristics of the population undergoing fertility work-up and identify screening and diagnostic strategies for TFI currently in place. The Netherlands is an exemplary model for the state of the art in high-income countries. Within the framework of existing clinical approaches, we propose a scenario for the translation of relevant genome-based information into triage of infertile women, with the objective of implementing genetic profiling in the routine investigation of TFI. Furthermore, we describe the state of the art in relevant gene- and single nucleotide polymorphism (SNP) based clinical prediction models and place our perspectives in the context of these applications. We conclude that the introduction of a genetic test of proven validity into the assessment of TFI should help reduce patient burden from invasive and costly examinations by achieving a more precise risk stratification.


Assuntos
Infecções por Chlamydia/genética , Chlamydia trachomatis/genética , Testes Genéticos , Infertilidade Feminina/genética , Anticorpos Antibacterianos/genética , Anticorpos Antibacterianos/imunologia , Infecções por Chlamydia/epidemiologia , Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/isolamento & purificação , Chlamydia trachomatis/patogenicidade , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/microbiologia , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único/genética
11.
J Assist Reprod Genet ; 36(6): 1127-1133, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31065945

RESUMO

PURPOSE: To evaluate the relationship of clinical pregnancy rates with bone morphogenetic proteins 2-4-7 (BMP 2, 4, 7), growth differentiation factor 9 (GDF 9), and Emmprin levels in follicular fluid of intracytoplasmic sperm injection patients. METHODS: Follicular fluid of 77 patients who underwent ICSI procedure was collected during the oocyte retrieval procedure. And follicular fluid levels of BMP 2, BMP 4, BMP 7, GDF 9, and Emmprin (Basigin) were measured and compared for clinical pregnancy rates. RESULTS: Follicular levels of BMP 4 was significantly higher whereas Emmprin levels were lower in patients who had achieved clinically diagnosed pregnancy compared with those who did not achieve clinical pregnancy after ICSI procedure (P = 0.007 and P = 0.035, respectively). BMP 2, BMP 7, and GDF 9 levels were comparable for both groups. CONCLUSION: Clinical pregnancy rates after ICSI may be associated with follicular fluid levels of Emmprin and BMP 4. Follicular levels of Emmprin and BMP 4 can be used as a marker (as markers for predicting ICSI outcomes) for a better ICSI outcome.


Assuntos
Basigina/genética , Proteína Morfogenética Óssea 4/genética , Infertilidade Feminina/genética , Taxa de Gravidez , Adulto , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 7/genética , Feminino , Fertilização In Vitro , Líquido Folicular/metabolismo , Fator 9 de Diferenciação de Crescimento/genética , Humanos , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/patologia , Masculino , Recuperação de Oócitos , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Indução da Ovulação/métodos , Gravidez , Injeções de Esperma Intracitoplásmicas/métodos
12.
Fertil Steril ; 112(2): 258-265, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31103285

RESUMO

OBJECTIVE: To evaluate differences in euploidy rates between IVF cycles triggered with either GnRH agonist (GnRHa) or hCG. DESIGN: Retrospective cohort study. SETTING: University-affiliated fertility center. PATIENT(S): A total of 366 patients performing 539 IVF cycles utilizing preimplantation genetic testing for aneuploidy (PGT-A). INTERVENTION(S): Gonadotropin-releasing hormone agonist or hCG trigger of oocyte maturation during IVF cycles. MAIN OUTCOME MEASURE(S): Rate of euploid embryos. RESULT(S): Patients in the GnRHa trigger arm were younger, with a lower body mass index and higher antimüllerian hormone level, and they had a higher number of oocytes retrieved and embryos biopsied. Euploid rate per embryo biopsied was higher after GnRHa trigger than after hCG trigger (37.8% ± 2.1% vs. 30.3% ± 1.8%), but multivariate regression analysis controlling for potential confounding factors did not show any differences between the two groups. Moreover, the euploid rate per oocyte retrieved was not significantly different overall (GnRHa vs. hCG: 33.9% ± 2.2% vs. 28.0% ± 1.9%). The anticipated decline in the rate of euploid embryos per oocyte retrieved went from 15.8% ± 1.2% for age <35 years to 4.3% ± 0.9% for patients aged ≥41 years. There were no significant differences between the two groups after stratifying by age and controlling for PGT-A testing modality. CONCLUSION(S): Both GnRHa and hCG trigger result in comparable euploid rates. Trigger with GnRHa should therefore be considered a valid option for trigger modality in freeze-all PGT-A cycles, in view of its demonstrated effectiveness and known safety enhancement.


Assuntos
Gonadotropina Coriônica/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Testes Genéticos/estatística & dados numéricos , Hormônio Liberador de Gonadotropina/uso terapêutico , Indução da Ovulação/métodos , Ploidias , Diagnóstico Pré-Implantação/estatística & dados numéricos , Adulto , Aneuploidia , Feminino , Fertilização In Vitro/estatística & dados numéricos , Humanos , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/genética , Infertilidade Feminina/terapia , Ciclo Menstrual/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Oogênese/genética , Indução da Ovulação/efeitos adversos , Indução da Ovulação/estatística & dados numéricos , Gravidez , Estudos Retrospectivos
13.
J Assist Reprod Genet ; 36(5): 915-924, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31025158

RESUMO

PURPOSE: To investigate the global transcriptome and associated embryonic molecular networks impacted with advanced maternal age (AMA). METHODS: Blastocysts derived from donor oocyte IVF cycles with no male factor infertility (< 30 years of age) and AMA blastocysts (≥ 42 years) with no other significant female factor infertility or male factor infertility were collected with informed patient consent. RNA sequencing libraries were prepared using the SMARTer® Ultra® Low Kit (Clontech Laboratories) and sequenced on the Illumina HiSEQ 4000. Bioinformatics included Ingenuity® Pathway Analysis (Qiagen) with ViiA™ 7 qPCR utilized for gene expression validation (Applied Biosystems). RESULTS: A total of 2688 significant differentially expressed transcripts were identified to distinguish the AMA blastocysts from young, donor controls. 2551 (95%) of these displayed decreased transcription in the blastocysts from older women. Pathway analysis revealed three altered molecular signaling networks known to be critical for embryo and fetal development: CREBBP, ESR1, and SP1. Validation of genes within these networks confirmed the global decreased transcription observed in AMA blastocysts (P < 0.05). CONCLUSIONS: A significant, overall decreased global transcriptome was observed in blastocysts from AMA women. The ESR1/SP1/CREBBP pathway, in particular, was found to be a highly significant upstream regulator impacting biological processes that are vital during embryonic patterning and pre-implantation development. These results provide evidence that AMA embryos are compromised on a cell signaling level which can repress the embryo's ability to proliferate and implant, contributing to a deterioration of reproductive outcomes.


Assuntos
Blastocisto/metabolismo , Regulação da Expressão Gênica , Infertilidade Feminina/genética , Infertilidade Masculina/genética , Idade Materna , Transcriptoma , Adulto , Implantação do Embrião , Desenvolvimento Embrionário , Feminino , Fertilização In Vitro , Perfilação da Expressão Gênica , Humanos , Masculino
14.
J Assist Reprod Genet ; 36(6): 1117-1125, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30963351

RESUMO

PURPOSE: To explore the attitudes of reproductive endocrinology and infertility (REI) and maternal-fetal medicine (MFM) subspecialists regarding the necessity and appropriateness of body mass index (BMI) cutoffs for women seeking fertility treatment. METHODS: Members of the Society for Reproductive Endocrinology and Infertility (SREI) and the Society for Maternal Fetal Medicine (SMFM) were invited to participate in a survey querying their knowledge of existing institutional or clinic BMI policies and personal opinions regarding upper and lower BMI cutoffs for a range of fertility treatments, including oral ovulation agents, gonadotropins, and in vitro fertilization. RESULTS: Respondents included 398 MFMs and 201 REIs. The majority of REI and MFM providers agreed with upper limit BMI cutoffs (72.5% vs 68.2%, p = 0.29), but REIs were twice as likely to support lower limit BMI restrictions compared to MFMs (56.2% vs 28.4%, p < 0.0001). Those who supported upper BMI restrictions were more likely to be female and report existing institutional BMI cutoffs. The majority of respondents (99.3%) believed that an official statement to guide clinicians should be issued by a national professional organization. CONCLUSIONS: Although practice patterns widely vary, the majority of REIs and MFMs believe that there should be a BMI cutoff above which women should not be offered immediate fertility treatment. Furthermore, there is a reported need for a written statement by a national professional organization to guide clinical practice and to ensure that OB/GYN subspecialists are providing consistent, fair, and safe recommendations to infertile women at the extremes of BMI.


Assuntos
Índice de Massa Corporal , Fertilidade/fisiologia , Infertilidade Feminina/epidemiologia , Técnicas de Reprodução Assistida/tendências , Adulto , Feminino , Fertilidade/genética , Fertilização In Vitro , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Masculino , Inquéritos e Questionários
15.
Horm Res Paediatr ; 91(1): 9-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947225

RESUMO

BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a heterogeneous disorder characterized by delayed or loss of puberty and infertility due to functional deficiency in the hypothalamic gonadotropin-releasing hormone (GnRH). CHH can be classified into 2 subtypes on the basis of olfaction: Kallmann syndrome and normosmic CHH (nCHH). The spectrum of genetic variants causing CHH is continually expanding. Here, we recruited a consanguineous Pakistani family having 2 male and 2 female infertile patients diagnosed with idiopathic nCHH. AIMS: The aim of this study was to investigate the genetic cause of nCHH in the family. METHODS: Clinical and physical analyses were performed for the patients. Genetic analysis was carried out using whole exome and Sanger sequencing. RESULTS: Clinical and physical investigations confirmed low levels of gonadotropins and failure of secondary sexual development in the patients. Genetic analysis identified a novel nonsense mutation (chr4: g.68619942G>A, c.112C>T, p.Arg38*) in the gonadotropin-releasing hormone receptor gene (GNRHR) recessively co-segregating with nCHH in this family. All the patients are homozygous and their parents are heterozygous carriers, while normal siblings are heterozygous carriers or wild-type for this mutation, indicating that the identified mutation is pathogenic for nCHH in the family. CONCLUSION: We report the first homozygous nonsense mutation in the GNRHR gene (chr4: g. 68619942G>A, c.112C>T, p. Arg38*) that is associated with familial nCHH. Hence, our study displayed a good correlation of the genotype and phenotype of nCHH patients.


Assuntos
Códon sem Sentido , Exoma , Família , Infertilidade Feminina/genética , Infertilidade Masculina/genética , Síndrome de Kallmann/genética , Receptores LHRH/genética , Adulto , Feminino , Humanos , Masculino , Paquistão , Sequenciamento Completo do Exoma
16.
Gen Comp Endocrinol ; 277: 130-140, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30951722

RESUMO

Expression of adamts9 (A disintegrin and metalloprotease with thrombospondin type-1 motif, member 9) increases dramatically in the somatic cells surrounding oocytes during ovulation in vertebrates from zebrafish to human. However, the function of Adamts9 during ovulation has not been determined due to the embryonic lethality of knockouts in mice and Drosophila. To identify the role of Adamts9 during ovulation we generated knockout (adamts9-/-) zebrafish using CRISPR/Cas9 and characterized the effects of the mutation. From 1047 fish generated by crossing adamts9+/- pairs, we found significantly fewer adult adamts9-/- fish (4%) than predicted by Mendelian ratios (25%). Of the mutants found, there was a significant male bias (82%). Only 3 female mutants were identified (7%), and they had small ovaries with few stage III and IV oocytes compared to wildtype (wt) counterparts of comparable size and age. Astoundingly, the remaining mutants (11%) did not appear to have normal testis or ovaries. Instead there was a pair of transparent, ovarian-like membranous shells that filled the abdominal cavity. Histological examination confirmed that shells were largely empty with no internal structure. Surprisingly, seminiferous tubules and various spermatocytes including mature spermatozoa were observed on the periphery of these transparent shells. No female or female like knockouts were observed to release eggs, and no ovulated oocytes were observed in histological sections. To our knowledge, this is the first report of an adamts9 global knockout model in any adult vertebrates and the first description of how gonadal sex and structure are affected- highlighting the importance of Adamts9 during gonadal development and the value of zebrafish as a model organism.


Assuntos
Proteína ADAMTS9/metabolismo , Ovário/embriologia , Ovário/metabolismo , Peixe-Zebra/metabolismo , Proteína ADAMTS9/deficiência , Proteína ADAMTS9/genética , Animais , Sequência de Bases , Feminino , Fertilização , Técnicas de Inativação de Genes , Homozigoto , Infertilidade Feminina/genética , Masculino , Mutação/genética , Ovário/anormalidades , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Razão de Masculinidade , Análise de Sobrevida
17.
Gene ; 703: 7-12, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-30951854

RESUMO

A successful embryo implantation depends on the synchronization between a competent blastocyst and a receptive endometrium. Recently, potential modulators of endometrial receptivity (OVGP1, MRAP2, ZCCHC12, and HAP1) have been reported likely with a functional role during embryo implantation. The aim of this study was to evaluate the gene expression of these genes in the endometrium of infertile women. Eighteen endometrial biopsies, during secretory lutheal phase, were recruited from women with unexplained infertility and women who cannot conceive due to their partners' fertility problems. qRT-PCR was carried out to evaluate MRAP2, OVGP1, ZCCHC12 and HAP1 gene expression. MRAP2 expression was also detected by western blot and it was localized by immunohistochemistry. Morphological analysis was performed by light microscopy. MRAP2 was significantly up-regulated in study vs. control group. Western blot analysis confirmed the observed MRAP2 up-expression. MRAP2 resulted mainly localized in the epithelial cells of uterine glands. Morphological analysis displayed that the epithelium of the uterine glands undergo hypertrophy in women with unexplained infertility in respect to women with male infertility factor. MRAP2 could be considered a mediator of endometrial receptivity likely acting on endometrial stability by binding to MCRs and PKR1.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Endométrio/metabolismo , Infertilidade Feminina/patologia , Adulto , Endométrio/citologia , Endométrio/patologia , Células Epiteliais/metabolismo , Feminino , Humanos , Hipertrofia , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , Regulação para Cima
18.
Fertil Steril ; 111(5): 982-990.e2, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30922641

RESUMO

OBJECTIVE: To evaluate the impact of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with clinical data analysis in controlled ovarian hyperstimulation (COH) of infertile women in the Intravenous Infusion Safety Evaluation Center of Hunan Province, People's Republic of China. DESIGN: Genetic Association Study. SETTING: Reproductive medicine clinical. PATIENT(S): This genetic association study included 722 infertile women who received the standard long treatment protocol with accessible and complete electronic medical records. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The clinical parameters were obtained from the Intravenous Infusion Safety Evaluation center. RESULT(S): Basal FSH levels in the TT group were significantly higher than those of the CC group. The FSH levels after down-regulation in the TT group were higher than those of CC/CT genotypes. The TT genotype patients received significantly higher total doses of GnRH agonist and FSH compared with CC/CT genotypes, whereas the total dose of hCG was higher in the CT genotypes compared with the CC/TT genotypes. Further association analysis between hormone levels and COH outcomes indicated significantly negative correlation of basal FSH levels with antral follicle count and number of oocytes as well as the down-regulation FSH levels with the number of metaphase II oocytes and oocytes. CONCLUSION(S): The MTHFR C677T polymorphism was associated with high doses of ovarian stimulation medications, as well as higher FSH levels. The negative correlation between FSH levels and the number of oocytes suggested that C677T polymorphism may play a role in the poor prognosis of COH oocytes. This needs to be studied in future prospective studies with longer follow-up.


Assuntos
Hormônio Foliculoestimulante/sangue , Estudos de Associação Genética/métodos , Infertilidade Feminina/sangue , Infertilidade Feminina/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Indução da Ovulação/métodos , Adulto , Biomarcadores/sangue , Bases de Dados Factuais , Feminino , Humanos , Infertilidade Feminina/terapia , Polimorfismo Genético/genética , Gravidez , Resultado da Gravidez , Estudos Retrospectivos
19.
Artigo em Inglês | MEDLINE | ID: mdl-30893922

RESUMO

The aim of this study was to examine the association between interleukin (IL) genes polymorphisms and in vitro fertilization (IVF) outcome. A prospective cohort analysis was performed at a Women's Hospital IVF centre of 1015 female patients undergoing fresh non-donor IVF cycles. The effects of the following six single nucleotide polymorphisms (SNPs) in five IL genes on IVF outcomes were explored: IL-1α (rs1800587 C/T), IL-3 (rs40401 C/T), IL-6 (rs1800795 C/G), IL-15 (rs3806798 A/T), IL-18 (rs187238 C/G) and IL-18 (rs1946518 G/T). The main outcome measures included clinical pregnancy, embryo implantation, abortion and live birth rates. There were no statistically significant differences in clinical pregnancy, embryo implantation and live birth rates in the analysis of 1015 patients attempting their first cycle of IVF. Infertile women with IL-3 homozygous major genotype had a higher abortion rate than those with heterozygous and homozygous minor genotype (16.5% vs. 7.9%, P = 0.025). In conclusion, our results indicated that the IL-3 rs40401 polymorphism is associated with increased risk of abortion of IVF patients. Future studies with inclusion of other ethnic populations must be conducted to confirm the findings of this study.


Assuntos
Aborto Espontâneo/genética , Fertilização In Vitro , Interleucina-3/genética , Polimorfismo de Nucleotídeo Único , Adulto , Implantação do Embrião , Feminino , Homozigoto , Humanos , Infertilidade Feminina/genética , Gravidez , Resultado da Gravidez , Estudos Prospectivos
20.
Fertil Steril ; 111(5): 1011-1019.e1, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30926125

RESUMO

OBJECTIVE: To study whether there is a difference in the prevalence of non-cavity-distorting uterine fibroids between infertile patients with polycystic ovary syndrome (PCOS) and those with unexplained infertility (UI). DESIGN: A secondary analysis of data from three randomized clinical trials. SETTING: Academic health centers. PATIENT(S): A total of 2,249 patients with normal uterine cavities. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The presence or absence of non-cavity-distorting fibroids. RESULT(S): Compared with women with UI, those with PCOS were younger, had a higher body mass index, and were more likely to be Hispanic or African American, with a lower percentage of previous conception and live birth, a higher percentage of current smokers, a lower percentage of current alcohol users, and higher total testosterone, fasting insulin, and homeostasis-model-assessment insulin resistance. The prevalence of women with non-cavity-distorting uterine fibroids was lower in women with PCOS than in those with UI (6.7% vs. 12.4%); this result held after patients were divided into Black and non-Black or into three different body mass index groups. After adjustment for all the other variables in the final model, patients with PCOS had a significantly lower prevalence of fibroids than those with UI (odds ratio 0.54). No differences in the prevalence of non-cavity-distorting fibroids with any dimensions ≥4 cm or the volume of the largest fibroid was found between the two groups. CONCLUSION(S): A lower prevalence of non-cavity-distorting uterine fibroids was found in infertile women with PCOS than in those with UI.


Assuntos
Infertilidade Feminina/diagnóstico , Infertilidade Feminina/epidemiologia , Leiomioma/diagnóstico , Leiomioma/epidemiologia , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/epidemiologia , Adulto , Grupo com Ancestrais do Continente Africano/genética , Método Duplo-Cego , Feminino , Humanos , Infertilidade Feminina/genética , Leiomioma/genética , Síndrome do Ovário Policístico/genética , Prevalência
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