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Hepatokines: the missing link in the development of insulin resistance and hyperandrogenism in PCOS?Hormones (Athens, Greece) Dec 2023The liver plays a critical role in several metabolic pathways, including the regulation of glucose and lipid metabolism. Non-alcoholic fatty liver disease (NAFLD), the... (Review)
Review
The liver plays a critical role in several metabolic pathways, including the regulation of glucose and lipid metabolism. Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, is closely associated with insulin resistance (IR) and metabolic syndrome (MetS). Hepatokines, newly discovered proteins secreted by hepatocytes, have been linked to the induction of these metabolic dysregulations. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, has been associated with NAFLD and IR, while hyperandrogenism additionally appears to be implicated in the pathogenesis of the latter. However, the potential role of hepatokines in the development of metabolic disorders in PCOS has not been fully investigated. Therefore, the aim of this review is to critically appraise the current evidence regarding the interplay of hepatokines with NAFLD, hyperandrogenism, and IR in PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Risk Factors
PubMed: 37704921
DOI: 10.1007/s42000-023-00487-x -
Genetics in Medicine : Official Journal... Aug 2023The aim of this study was to assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCAs) in an unselected obstetrical...
PURPOSE
The aim of this study was to assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCAs) in an unselected obstetrical population with genetic confirmation.
METHODS
This was a planned secondary analysis of the multicenter, prospective SNP-based Microdeletion and Aneuploidy RegisTry (SMART) study. Patients receiving cfDNA results for autosomal aneuploidies and who had confirmatory genetic results for the relevant sex chromosomal aneuploidies were included. Screening performance for SCAs, including monosomy X (MX) and the sex chromosome trisomies (SCT: 47,XXX; 47,XXY; 47,XYY) was determined. Fetal sex concordance between cfDNA and genetic screening was also evaluated in euploid pregnancies.
RESULTS
A total of 17,538 cases met inclusion criteria. Performance of cfDNA for MX, SCTs, and fetal sex was determined in 17,297, 10,333, and 14,486 pregnancies, respectively. Sensitivity, specificity, and positive predictive value (PPV) of cfDNA were 83.3%, 99.9%, and 22.7% for MX and 70.4%, 99.9%, and 82.6%, respectively, for the combined SCTs. The accuracy of fetal sex prediction by cfDNA was 100%.
CONCLUSION
Screening performance of cfDNA for SCAs is comparable to that reported in other studies. The PPV for the SCTs was similar to the autosomal trisomies, whereas the PPV for MX was substantially lower. No discordance in fetal sex was observed between cfDNA and postnatal genetic screening in euploid pregnancies. These data will assist interpretation and counseling for cfDNA results for sex chromosomes.
Topics: Pregnancy; Female; Humans; Trisomy; Noninvasive Prenatal Testing; Prospective Studies; Chromosome Disorders; Sex Chromosome Aberrations; Aneuploidy; Sex Chromosomes; Turner Syndrome; Cell-Free Nucleic Acids; Prenatal Diagnosis
PubMed: 37154148
DOI: 10.1016/j.gim.2023.100879 -
Cancer Oct 2023Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of...
BACKGROUND
Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics.
METHODS
Birth defect-GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and by genetic and chromosomal syndromes and nonsyndromic defects. Stratification was by sex, tumor histology (yolk sac tumor, teratoma, germinoma, and mixed/other), and location (gonadal, extragonadal, and intracranial).
RESULTS
Birth defects and syndromic defects were more common among GCT cases than controls (6.9% vs. 4.0% and 2.7% vs. 0.2%, respectively; both p < .001). In multivariable models, GCT risk was increased among children with birth defects (OR, 1.7; 95% CI, 1.3-2.4) and syndromic defects (OR, 10.4; 95% CI, 4.9-22.1). When stratified by tumor characteristics, birth defects were associated with yolk sac tumors (OR, 2.7; 95% CI, 1.3-5.0) and mixed/other histologies (OR, 2.1; 95% CI, 1.2-3.5) and both gonadal tumors (OR, 1.7; 95% CI, 1.0-2.7) and extragonadal tumors (OR, 3.8; 95% CI, 2.1-6.5). Nonsyndromic defects specifically were not associated with GCTs. In sex-stratified analyses, associations were observed among males but not females.
CONCLUSIONS
These data suggest that males with syndromic birth defects are at an increased risk of pediatric GCTs, whereas males with nonsyndromic defects and females are not at an increased risk.
PLAIN LANGUAGE SUMMARY
We investigated whether birth defects (such as congenital heart disease or Down syndrome) are linked to childhood germ cell tumors (GCTs), cancers that mainly develop in the ovaries or testes. We studied different types of birth defects (defects that were caused by chromosome changes such as Down syndrome or Klinefelter syndrome and defects that were not) and different types of GCTs. Only chromosome changes such as Down syndrome or Klinefelter syndrome were linked to GCTs. Our study suggests that most children with birth defects are not at an increased risk of GCTs because most birth defects are not caused by chromosome changes.
Topics: Male; Child; Humans; Adolescent; Klinefelter Syndrome; Down Syndrome; Neoplasms, Germ Cell and Embryonal; Testicular Neoplasms
PubMed: 37366624
DOI: 10.1002/cncr.34906 -
Frontiers in Endocrinology 2024Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent... (Review)
Review
Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent only a small number of these diseases. Due to the rarity of non-CAH 46,XX DSD, data on this sex chromosomal aberration were confined to case reports or case series with small numbers of patients. As the literature is still relatively sparse, medical data on the long-term effects of these pathologies remain scarce. In this review, we aim to provide an overview of current data on the long-term follow-up of patients with non-CAH 46,XX DSD, by covering the following topics: quality of life, gender identity, fertility and sexuality, global health, bone and cardiometabolic effects, cancer risk, and mortality. As non-CAH 46,XX DSD is a very rare condition, we have no accurate data on adult QoL assessment for these patients. Various factors may contribute to a legitimate questioning about their gender identity, which may differ from their sex assigned at birth. A significant proportion of gender dysphoria has been reported in various series of 46,XX DSD patients. However, it is difficult to give an accurate prevalence of gender dysphoria and gender reassignment in non-CAH 46,XX DSD because of the rarity of the data. Whatever the aetiology of non-CAH 46,XX DSD, fertility seems to be impaired. On the other hand, sexuality appears preserved in 46,XX men, whereas it is impaired in women with MRKH syndrome before treatment. Although there is still a paucity of data on general health, bone and cardiometabolic effects, and mortality, it would appear that the 46,XX DSD condition is less severely affected than other DSD conditions. Further structured and continued multi-center follow-up is needed to provide more information on the long-term outcome of this very rare non-CAH 46,XX DSD condition.
Topics: Female; Humans; Male; 46, XX Disorders of Sex Development; Adrenal Hyperplasia, Congenital; Disorders of Sex Development; Fertility; Gender Identity; Quality of Life
PubMed: 38752171
DOI: 10.3389/fendo.2024.1372887 -
Frontiers in Endocrinology 2023Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and... (Review)
Review
Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.
Topics: Female; Pregnancy; Humans; Adrenal Hyperplasia, Congenital; Antley-Bixler Syndrome Phenotype; Rupture, Spontaneous; Karyotype; Disorders of Sex Development; Cysts
PubMed: 37635957
DOI: 10.3389/fendo.2023.1226387 -
Biomedicine & Pharmacotherapy =... Nov 2023Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorder in women of childbearing age, with ovulatory dysfunction, hyperandrogenism, and... (Review)
Review
Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorder in women of childbearing age, with ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology (PCOM) as the clinical features. Androgen excess, insulin resistance, obesity, adipose tissue dysfunction, ovulatory dysfunction, and gut microbiota dysbiosis are the main pathological features and pathogenesis of PCOS and are related to systemic chronic low-grade inflammation and chronic ovarian tissue inflammation in PCOS. With the advances in immune-endocrine interaction studies, research on the role of immune cells in the occurrence and development of PCOS is gradually increasing. As the core of innate immunity, macrophages play an indispensable role in systemic inflammatory response. Meanwhile, they are involved in maintaining the stability and function of the ovary as the most abundant immune cells in ovarian tissue. Studies in humans and mice have found that the polarization of macrophages into M1 type plays multiple roles in the pathogenesis of PCOS. This review describes the distribution characteristics of macrophage subpopulations in patients and animal models with PCOS, discusses the role of macrophage-related metabolic inflammation in PCOS, and summarizes the relationship between macrophages and PCOS-related pathological features and its possible mechanisms, to further understand the pathogenesis of PCOS and reveal the role of macrophages in it. In addition, research on immune-endocrine interactions can also provide direction for finding new therapeutic targets for PCOS.
Topics: Female; Humans; Mice; Animals; Polycystic Ovary Syndrome; Hyperandrogenism; Insulin Resistance; Macrophages; Inflammation
PubMed: 37716116
DOI: 10.1016/j.biopha.2023.115470 -
Indian Journal of Pediatrics Oct 2023Disorders of sex development (DSD) is a broad term for congenital conditions with a discrepancy in chromosomal, gonadal, or anatomic sex. Pediatricians are often faced... (Review)
Review
Disorders of sex development (DSD) is a broad term for congenital conditions with a discrepancy in chromosomal, gonadal, or anatomic sex. Pediatricians are often faced with the challenge of managing a newborn/infant with atypical genitalia or an older child with disordered puberty, which come under the purview of DSD. This article provides an update for pediatricians on comprehensive approach to DSD with a focus on atypical genitalia.
Topics: Child; Infant, Newborn; Humans; Adolescent; Disorders of Sex Development; Sexual Development
PubMed: 37354346
DOI: 10.1007/s12098-023-04640-7 -
Scientific Reports Aug 2023Polycystic ovary syndrome (PCOS) is a highly complex reproductive metabolic disorder and women with PCOS have high prevalence of non-alcoholic fatty liver disease...
Polycystic ovary syndrome (PCOS) is a highly complex reproductive metabolic disorder and women with PCOS have high prevalence of non-alcoholic fatty liver disease (NAFLD). Despite both hyperandrogenism and insulin resistance are common pathophysiologies in NAFLD and PCOS, this association is still controversial. Therefore, the aim of this study is to evaluate the relationship between hyperandrogenism and NAFLD in females diagnosed with PCOS. We recruited 667 women diagnosed with PCOS and 289 women with regular menstrual cycles as control. The PCOS diagnosis was made using National Institute of Child Health and Human Disease criteria. Total and free testosterone levels (TT and TF, respectively), and free androgen index (FAI) were used as measures of hyperandrogenism. Fatty liver index and liver fat score (FLI and LFS, respectively), and hepatic steatosis index (HSI) were used to assess NAFLD. The prevalence of NAFLD in PCOS women evaluated by LFS, FLI, and HIS were 19.9, 10.3, and 32.2%, respectively. In the control group, the incidence was 2.1, 0.7, and 4.2%, respectively. Both FT and FAI levels showed significant association with increased NAFLD-related indices, after adjusting for insulin resistance and other factors (LFS (OR 3.18 (95% CI 1.53-6.63) in FT; 1.12 (1.04-1.22) in FAI), FLI (OR 2.68 (95% CI 1.43-5.03) in FT; 1.13 (1.06-1.20) in FAI), and HSI (OR 3.29 (95% CI 2.08-5.21) in FT; 1.5 (1.09-1.21) in FAI). TT did not exhibit association with any NAFLD index. In women with PCOS, significantly higher rate of NAFLD was observed compared to the control women. The FT and FAI were independently associated with NAFLD in women with PCOS. The findings suggest the possibility of hyperandrogenism contributing to the progression and/or development of NAFLD in PCOS.
Topics: Child; Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Non-alcoholic Fatty Liver Disease; Insulin Resistance
PubMed: 37591864
DOI: 10.1038/s41598-023-39428-4 -
Frontiers in Endocrinology 2023Turner syndrome (TS) is a genetic pathology that affects about 1/2500 newborn females. Turner's syndrome is characterized by highly variable genetic anomalies that... (Review)
Review
Turner syndrome (TS) is a genetic pathology that affects about 1/2500 newborn females. Turner's syndrome is characterized by highly variable genetic anomalies that consist in a partial or complete deletion of the X sexual chromosome; it can be present as a monosomy or as a mosaicism with two o three different cellular lines. 50% of the patients with Turner's syndrome has a 45 XO karyotype while the remaining cases have karyotypes with mosaicism or X isochromosome or with partial or whole Y chromosome. This pathology is characterized by multiple anomalies that involve physical and cognitive development and in particular endocrine, cardiovascular, reproductive, auditive and visual systems. Integrity of the X chromosome in essential for fertility. In TS is accelerated germ cells apoptosis. About 30% of TS girls have some pubertal development, 10-20% undergo menarche and 2-8% go through spontaneous pregnancy. Women with TS should be informed about the risk of premature menopause and should be referred, if possible, to a specialist evaluation with a doctor expert in assisted reproductive techniques. In adolescents and in adults, Premature Ovarian Insufficiency (POI) can be evaluated clinically and biochemically with the classic combination of amenorrhea and elevated FSH concentrations (hypergonadotropic hypogonadism). However, in postpubertal adolescents and adult women, reproductive hormones may remain within the normal range before POI is clinically evident, despite significant depletion of the ovarian reserve. Today, reproductive medicine offers the opportunity of fertility preservation in women with premature ovarian insufficiency (POI). Two techniques have been suggested such as ovarian cortex cryopreservation and oocytes cryopreservation.
Topics: Pregnancy; Adult; Infant, Newborn; Adolescent; Humans; Female; Turner Syndrome; Reproductive Health; Primary Ovarian Insufficiency; Puberty; Menopause, Premature
PubMed: 38116311
DOI: 10.3389/fendo.2023.1269009 -
ELife Oct 2023DMRT1 is the testis-determining factor in several species of vertebrates, but its involvement in mammalian testes differentiation, where is the testis-determining gene,...
DMRT1 is the testis-determining factor in several species of vertebrates, but its involvement in mammalian testes differentiation, where is the testis-determining gene, remains ambiguous. So far, DMRT1 loss-of-function has been described in two mammalian species and induces different phenotypes: Disorders of Sex Development (46, XY DSD) in men and male infertility in mice. We thus abolished DMRT1 expression by CRISPR/Cas9 in a third species of mammal, the rabbit. First, we observed that gonads from XY rabbit fetuses differentiated like ovaries, highlighting that DMRT1 is involved in testis determination. In addition to SRY, DMRT1 is required in the supporting cells to increase the expression of the gene, which heads the testicular genetic cascade. Second, we highlighted another function of DMRT1 in the germline since XX and XY ovaries did not undergo meiosis and folliculogenesis. XX adult females were sterile, showing that DMRT1 is also crucial for female fertility. To conclude, these phenotypes indicate an evolutionary continuum between non-mammalian vertebrates such as birds and non-rodent mammals. Furthermore, our data support the potential involvement of mutations in different human pathologies, such as 46, XY DSD as well as male and female infertility.
Topics: Animals; Female; Male; Rabbits; Disorder of Sex Development, 46,XY; Fertility; Gene Expression Regulation, Developmental; Gonads; Mammals; Sex Determination Processes; SOX9 Transcription Factor; Testis
PubMed: 37847154
DOI: 10.7554/eLife.89284