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Revista de Investigacion Clinica;... 2017Young women with breast cancer have age-specific concerns regarding changes in sexuality, fertility, and body image. However, the psychological impact of BC and its... (Review)
Review
Young women with breast cancer have age-specific concerns regarding changes in sexuality, fertility, and body image. However, the psychological impact of BC and its treatments is not exclusive to young patients and it also affects their social context, especially their partners, as they experience higher illness intrusiveness than the partners of older women. In young BC patients, relationships, body image, and sexual problems are related to most quality of life domains. While BC treatment is being planned, all women should be informed about the possible side-effects of treatment on sexuality, fertility, and body image. Inclusion of partners into decision making should be pursued to restore, improve, and maintain effective communication and positive relationships in young couples facing BC. The aim of this review is to describe the psychological impact of alterations in sexuality, fertility, and body image in young BC patients and their partners, and to recommend strategies to address such issues in a timely manner.
Topics: Adult; Age of Onset; Body Image; Breast Neoplasms; Female; Fertility; Humans; Quality of Life; Sexual Partners; Sexuality
PubMed: 28776605
DOI: 10.24875/ric.17002279 -
Frontiers in Immunology 2021Varicocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to... (Review)
Review
BACKGROUND
Varicocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system.
RESULTS
The testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB).
CONCLUSIONS
The testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.
Topics: Animals; Cellular Microenvironment; Fertility; Humans; Immunotherapy; Infertility, Male; Inflammation Mediators; Male; Orchitis; Signal Transduction; Testis; Varicocele
PubMed: 34531872
DOI: 10.3389/fimmu.2021.729539 -
The New England Journal of Medicine Jul 2020Uterine fibroids, the most common type of tumor among women of reproductive age, are associated with heavy menstrual bleeding, abdominal discomfort, subfertility, and a... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Uterine fibroids, the most common type of tumor among women of reproductive age, are associated with heavy menstrual bleeding, abdominal discomfort, subfertility, and a reduced quality of life. For women who wish to preserve their uterus and who have not had a response to medical treatment, myomectomy and uterine-artery embolization are therapeutic options.
METHODS
We conducted a multicenter, randomized, open-label trial to evaluate myomectomy, as compared with uterine-artery embolization, in women who had symptomatic uterine fibroids and did not want to undergo hysterectomy. Procedural options included open abdominal, laparoscopic, or hysteroscopic myomectomy. The primary outcome was fibroid-related quality of life, as assessed by the score on the health-related quality-of-life domain of the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire (scores range from 0 to 100, with higher scores indicating a better quality of life) at 2 years; adjustment was made for the baseline score.
RESULTS
A total of 254 women, recruited at 29 hospitals in the United Kingdom, were randomly assigned: 127 to the myomectomy group (of whom 105 underwent myomectomy) and 127 to the uterine-artery embolization group (of whom 98 underwent embolization). Data on the primary outcome were available for 206 women (81%). In the intention-to-treat analysis, the mean (±SD) score on the health-related quality-of-life domain of the UFS-QOL questionnaire at 2 years was 84.6±21.5 in the myomectomy group and 80.0±22.0 in the uterine-artery embolization group (mean adjusted difference with complete case analysis, 8.0 points; 95% confidence interval [CI], 1.8 to 14.1; P = 0.01; mean adjusted difference with missing responses imputed, 6.5 points; 95% CI, 1.1 to 11.9). Perioperative and postoperative complications from all initial procedures, irrespective of adherence to the assigned procedure, occurred in 29% of the women in the myomectomy group and in 24% of the women in the uterine-artery embolization group.
CONCLUSIONS
Among women with symptomatic uterine fibroids, those who underwent myomectomy had a better fibroid-related quality of life at 2 years than those who underwent uterine-artery embolization. (Funded by the National Institute for Health Research Health Technology Assessment program; FEMME Current Controlled Trials number, ISRCTN70772394.).
Topics: Adult; Female; Humans; Hysteroscopy; Intention to Treat Analysis; Intraoperative Complications; Laparoscopy; Leiomyoma; Length of Stay; Menorrhagia; Middle Aged; Ovarian Reserve; Postoperative Complications; Quality of Life; Reoperation; Uterine Artery Embolization; Uterine Myomectomy; Uterine Neoplasms; Uterus
PubMed: 32726530
DOI: 10.1056/NEJMoa1914735 -
Molecular Cell Sep 2017Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the...
Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the chromodomain Y-like transcription corepressor CDYL negatively regulates histone Kcr by acting as a crotonyl-CoA hydratase to convert crotonyl-CoA to β-hydroxybutyryl-CoA. We showed that the negative regulation of histone Kcr by CDYL is intrinsically linked to its transcription repression activity and functionally implemented in the reactivation of sex chromosome-linked genes in round spermatids and genome-wide histone replacement in elongating spermatids. Significantly, Cdyl transgenic mice manifest dysregulation of histone Kcr and reduction of male fertility with a decreased epididymal sperm count and sperm cell motility. Our study uncovers a biochemical pathway in the regulation of histone Kcr and implicates CDYL-regulated histone Kcr in spermatogenesis, adding to the understanding of the physiology of male reproduction and the mechanism of the spermatogenic failure in AZFc (Azoospermia Factor c)-deleted infertile men.
Topics: Acyl Coenzyme A; Animals; Co-Repressor Proteins; Enoyl-CoA Hydratase; Fertility; Genetic Predisposition to Disease; HeLa Cells; Histone Acetyltransferases; Histones; Humans; Hydro-Lyases; Infertility, Male; Kinetics; Lysine; Male; Mice, Inbred C57BL; Mice, Transgenic; Phenotype; Protein Domains; Protein Processing, Post-Translational; Proteins; RNA Interference; Sf9 Cells; Sperm Count; Sperm Motility; Spermatogenesis; Spermatozoa; Testis; Transfection
PubMed: 28803779
DOI: 10.1016/j.molcel.2017.07.011 -
Molecular Cell May 2022The functional consequence of N-methyladenosine (mA) RNA modification is mediated by "reader" proteins of the YTH family. YTH domain-containing 2 (YTHDC2) is essential...
The functional consequence of N-methyladenosine (mA) RNA modification is mediated by "reader" proteins of the YTH family. YTH domain-containing 2 (YTHDC2) is essential for mammalian fertility, but its molecular function is poorly understood. Here, we identify U-rich motifs as binding sites of YTHDC2 on 3' UTRs of mouse testicular RNA targets. Although its YTH domain is an mA-binder in vitro, the YTH point mutant mice are fertile. Significantly, the loss of its 3'→5' RNA helicase activity causes mouse infertility, with the catalytic-dead mutation being dominant negative. Biochemical studies reveal that the weak helicase activity of YTHDC2 is enhanced by its interaction with the 5'→3' exoribonuclease XRN1. Single-cell transcriptomics indicate that Ythdc2 mutant mitotic germ cells transition into meiosis but accumulate a transcriptome with mixed mitotic/meiotic identity that fail to progress further into meiosis. Finally, our demonstration that ythdc2 mutant zebrafish are infertile highlights its conserved role in animal germ cell development.
Topics: Animals; DNA-Binding Proteins; Exoribonucleases; Fertility; Mammals; Meiosis; Mice; RNA; RNA Helicases; Zebrafish
PubMed: 35305312
DOI: 10.1016/j.molcel.2022.02.034 -
PLoS Genetics Aug 2018During meiosis, maternal and paternal chromosomes undergo exchanges by homologous recombination. This is essential for fertility and contributes to genome evolution. In... (Review)
Review
During meiosis, maternal and paternal chromosomes undergo exchanges by homologous recombination. This is essential for fertility and contributes to genome evolution. In many eukaryotes, sites of meiotic recombination, also called hotspots, are regions of accessible chromatin, but in many vertebrates, their location follows a distinct pattern and is specified by PR domain-containing protein 9 (PRDM9). The specification of meiotic recombination hotspots is achieved by the different activities of PRDM9: DNA binding, histone methyltransferase, and interaction with other proteins. Remarkably, PRDM9 activity leads to the erosion of its own binding sites and the rapid evolution of its DNA-binding domain. PRDM9 may also contribute to reproductive isolation, as it is involved in hybrid sterility potentially due to a reduction of its activity in specific heterozygous contexts.
Topics: Amino Acid Sequence; Animals; Binding Sites; Chromosome Mapping; DNA-Binding Proteins; Evolution, Molecular; Fertility; Heterozygote; Histone-Lysine N-Methyltransferase; Homologous Recombination; Humans; Infertility; Male; Meiosis; Mice; Protein Conformation; Reproductive Isolation; Spermatocytes
PubMed: 30161134
DOI: 10.1371/journal.pgen.1007479 -
Fertility and Sterility May 2015Many women now choose to develop their careers before having children. Thus, it is becoming increasingly important to assess a woman's potential for extended fertility... (Review)
Review
Many women now choose to develop their careers before having children. Thus, it is becoming increasingly important to assess a woman's potential for extended fertility and to understand the health consequences of having children at a late age. In particular, there is a striking positive correlation between extended fertility and longevity in women, which poses important implications for medicine, biology, and evolution. In this article we review the diverse epidemiologic evidence for the link between fertility potential, age of menopause, and women's lifespan. Then we discuss the recent advances using genomic technology to better understand biological mechanisms driving this association. At the genetic level, there are polymorphisms that may be driving both extended fertility and longevity. At the cellular and molecular levels, changes in the genome (both nuclear and mitochondrial), epigenome, and transcriptome during oocyte aging have important implications for fertility. By synthesizing results from diverse domains, we hope to provide a genomic-era conceptual framework in which this important connection can be investigated and understood.
Topics: Adult; Biological Evolution; DNA, Mitochondrial; Epigenesis, Genetic; Female; Fertility; Genetic Markers; Genome-Wide Association Study; Genotype; Humans; Longevity; Maternal Age; Menopause; Middle Aged; Oocytes; Phenotype; Polymorphism, Genetic; Pregnancy; Telomere
PubMed: 25796320
DOI: 10.1016/j.fertnstert.2015.02.008 -
Sexual Development : Genetics,... 2022Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases.... (Review)
Review
Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination.
Topics: Male; Humans; MAP Kinase Kinase Kinase 1; Gonadal Dysgenesis, 46,XY; Gonadal Dysgenesis; Heterozygote; Testis
PubMed: 35290982
DOI: 10.1159/000522428 -
Genes Aug 2021All mammalian oocytes and eggs are surrounded by a relatively thick extracellular matrix (ECM), the zona pellucida (ZP), that plays vital roles during oogenesis,... (Review)
Review
All mammalian oocytes and eggs are surrounded by a relatively thick extracellular matrix (ECM), the zona pellucida (ZP), that plays vital roles during oogenesis, fertilization, and preimplantation development. Unlike ECM surrounding somatic cells, the ZP is composed of only a few glycosylated proteins, ZP1-4, that are unique to oocytes and eggs. ZP1-4 have a large region of polypeptide, the ZP domain (ZPD), consisting of two subdomains, ZP-N and ZP-C, separated by a short linker region, that plays an essential role in polymerization of nascent ZP proteins into crosslinked fibrils. Both subdomains adopt immunoglobulin (Ig)-like folds for their 3-dimensional structure. Mouse and human genes are encoded by single-copy genes located on different chromosomes and are highly expressed in the ovary by growing oocytes during late stages of oogenesis. Genes encoding ZP proteins are conserved among mammals, and their expression is regulated by -acting sequences located close to the transcription start-site and by the same/similar -acting factors. Nascent ZP proteins are synthesized, packaged into vesicles, secreted into the extracellular space, and assembled into long, crosslinked fibrils that have a structural repeat, a ZP2-ZP3 dimer, and constitute the ZP matrix. Fibrils are oriented differently with respect to the oolemma in the inner and outer layers of the ZP. Sequence elements in the ZPD and the carboxy-terminal propeptide of ZP1-4 regulate secretion and assembly of nascent ZP proteins. The presence of both ZP2 and ZP3 is required to assemble ZP fibrils and ZP1 and ZP4 are used to crosslink the fibrils. Inactivation of mouse genes by gene targeting has a detrimental effect on ZP formation around growing oocytes and female fertility. Gene sequence variations in human genes due to point, missense, or frameshift mutations also have a detrimental effect on ZP formation and female fertility. The latter mutations provide additional support for the role of ZPD subdomains and other regions of ZP polypeptide in polymerization of human ZP proteins into fibrils and matrix.
Topics: Animals; Female; Fertility; Humans; Mammals; Mice; Oocytes; Oogenesis; Zona Pellucida
PubMed: 34440440
DOI: 10.3390/genes12081266 -
Cell Death & Disease Apr 2023Female subfertility is an increasing reproductive issue worldwide, which is partially related to abnormal ovarian follicular development. Granulosa cells (GCs), by...
Female subfertility is an increasing reproductive issue worldwide, which is partially related to abnormal ovarian follicular development. Granulosa cells (GCs), by providing the necessary physical support and microenvironment for follicular development, play critical roles in maintaining female fertility. We previously showed that ectopic expression of four and a half LIM domains 2 (FHL2) promoted ovarian granulosa cell tumor progression. However, its function in follicular development and fertility remains unknown. Here, we confirmed that FHL2 is highly expressed in human and mouse ovaries. FHL2 immunosignals were predominantly expressed in ovarian GCs. A Fhl2 knockout (KO) mouse model was generated to examine its roles in follicular development and fertility. Compared with wildtype, knockout of Fhl2 significantly decreased female litter size and offspring number. Furthermore, Fhl2 deficiency reduced ovarian size and impaired follicular development. RNA-sequencing analysis of GCs isolated from either KO or WT mice revealed that, Fhl2 deletion impaired multiple biological functions and signaling pathways, such as Ovarian Putative Early Atresia Granulosa Cell, ErbB, Hippo/YAP, etc. In vitro studies confirmed that FHL2 silencing suppressed GCs growth and EGF-induced GCs proliferation, while its overexpression promoted GC proliferation and decreased apoptosis. Mechanistic studies indicated that FHL2, via forming complexes with transcriptional factors AP-1 or NF-κB, regulated Egf and Egfr expression, respectively. Besides, FHL2 depletion decreased YAP1 expression, especially the active form of YAP1 (nuclear YAP1) in GCs of growing follicles. EGF, serving as an autocrine/paracrine factor, not only induced FHL2 expression and nuclear accumulation, but also stimulated YAP1 expression and activation. Collectively, our study suggests that FHL2 interacts with EGFR and Hippo/YAP signaling to regulate follicular development and maintain fertility. This study illuminates a novel mechanism for follicular development and a potential therapeutic target to address subfertility.
Topics: Female; Humans; Mice; Animals; Epidermal Growth Factor; Granulosa Cells; ErbB Receptors; Transcription Factor AP-1; Fertility; Muscle Proteins; Transcription Factors; LIM-Homeodomain Proteins
PubMed: 37015904
DOI: 10.1038/s41419-023-05759-3