The objective of this study was to identify new environmental and genetic risk factors for orofacial clefts that arise during early foetal development. In this retrospective, case–control, ...mother–child pair study, 172 orofacial clefts cases and 199 healthy controls, and their respective mothers, were genotyped for common variants in relevant genes obtained by text and database mining using STRING 10.0. Exposure to environmental risk factors was evaluated using questionnaires. Variant glycine N-methyltransferase (odds ratio (OR) 2.1, 95% confidence interval (95% CI) 1.0–4.4) and dihydrofolate reductase (OR 2.4, 95% CI 1.3–4.5) genotypes were identified as risk factors for cleft lip with or without cleft palate formation. Furthermore, synergy was detected between variant glycine N-methyltransferase and dihydrofolate reductase genotypes in promoting cleft lip with or without cleft palate formation (OR 7, 95% CI 2–23). This study is novel in finding that common glycine N-methyltransferase variant genotypes increase the risk of cleft lip with or without cleft palate.
Folate is vital for cell development and growth. It is involved in one-carbon transfer reactions essential for the synthesis of purines and pyrimidines. It also acts in conjunction with cobalamin ...(vitamin B
12
) as a fundamental cofactor in the remethylation cycle that converts homocysteine to methionine. A deficiency in folate or vitamin B
12
can lead to elevated homocysteine level, which has been identified as an independent risk factor in several health-related conditions. Adequate folate levels are essential in women of childbearing age and in pregnant women, and folate deficiency is associated with several congenital malformations. Low folate levels can be caused by dietary deficiencies, a genetic predisposition or treatment with medicines that affect folate concentration. Women who are pregnant or of child-bearing age commonly use medicines, so it is important to identify the basic biochemical mechanisms by which medicines interfere with the folate–homocysteine–methionine pathway. This review focuses on prescription medicines associated with folate disruption. It also summarizes their undesirable/toxic effects. Recommendations regarding folate supplementation during medical therapy are also reviewed.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with increased prevalence of insulin resistance (IR). IR could be implicated in PCOS etiology and represents the major cause ...of cardiometabolic complications. The aim of present study was to investigate for the first time the association of lipin 1 gene polymorphisms with metabolic and hormonal profile in PCOS patients and controls. Into a case-control study 371 individuals were enrolled: 222 PCOS patients and 149 controls. Two lipin 1 gene polymorphisms were analyzed: rs11693809 (intron 1 SNP) and rs2716610 (intron 17 SNP) using fluorescent hydrolyzing probes. Body mass index, fasting plasma insulin and glucose along with androgen profile were measured in all subjects. Plasma lipids were measured in 93 patients and 43 controls and oral glucose test (OGTT) was performed on 68 PCOS patients. C/T heterozygotes for intron 1 SNP had significantly lower LDL-cholesterol than wild type C/C homozygotes (p=0.026) in the control group. In PCOS patients, mutated T/T homozygotes exhibited significantly lower glucose after OGTT than heterozygotes (p=0.033). Similarly, in nonobese PCOS patients, intron 1 SNP T/T homozygotes had lower HOMA-IR than heterozygotes (p=0.009). For intron 17 SNP, mutated C/T+T/T genotypes were associated with higher plasma triglycerides in controls (p=0.039). Genotype and allele frequencies were similar between PCOS patients and controls for both SNPs. Our results show that, in PCOS patients, intron 1 SNP is protective against IR and glucose intolerance suggesting that lipin 1 variation could be one of the genetic factors in cardiometabolic complications of PCOS.
Abstract
STUDY QUESTION
What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature?
SUMMARY ANSWER
The ...evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI.
WHAT IS KNOWN ALREADY
UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after ‘standard’ investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation.
STUDY DESIGN, SIZE, DURATION
The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee.
MAIN RESULTS AND THE ROLE OF CHANCE
This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations—of which 29 were formulated as strong recommendations and 11 as weak—10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided.
LIMITATIONS, REASONS FOR CAUTION
Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised.
WIDER IMPLICATIONS OF THE FINDINGS
The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI.
STUDY FUNDING/COMPETING INTEREST(S)
The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women’s Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers’ fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers’ fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker’s fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker’s fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker’s fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker’s fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers’ fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose.
DISCLAIMER
This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained.
Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type.
ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at
www.eshre.eu/guidelines.)
Abstract Low-level X chromosome mosaicism and its clinical relevance are still under debate. It could be interpreted as a technical artefact, genuine mosaicism or as being age-related. This study ...evaluated the contribution of X chromosome mosaicism in phenotypically normal women with sporadic premature ovarian failure (POF). During 1999–2008, 114 patients with POF and 64 age matched controls were karyotyped. Thirteen patients (11.4%) had true X chromosome mosaicism (>10% of aneuploid cells) and 12 had (10.5%) low-level X-mosaicism (between 6–10% of aneuploid cells). The mean age of women with true and low-level mosaicism was 26.0 ± 5.65 years and 35.92 ± 3.87 years, respectively ( P < 0.001). In the control group the incidence of cells with an abnormal number of X chromosomes was 1–3%. The results have practical implications for genetic counselling and fertility treatment. To search and confirm the low-level mosaicism, a higher number of metaphases should be analysed or additional fluorescence in-situ hybridization analysis must be performed. Although peripheral blood does not reflect the situation in ovarian tissue well, it is presumed that there are different aetiological causes for true and low-level X chromosome mosaicism. The possible causes and reproductive significance of low-level X chromosome mosaicism are discussed. X chromosome abnormalities are usually associated with abnormal sexual development and reproductive performance, such as amenorrhoea, infertility, recurrent abortions and premature ovarian failure. X chromosome mosaicism is the presence of two populations of cells in the body. Some cells have two X chromosomes while others have only one X chromosome. Low-level X chromosome mosaicism (less than 10% of cells have one X chromosome) and its clinical relevance are still under debate. It could be interpreted as a technical artefact, genuine mosaicism or as being age-related. We evaluated the contribution of X chromosome mosaicism in women with premature ovarian failure (POF). In the period between 1999 and 2008, the chromosomes of 114 patients with POF and 64 age matched controls were analysed. Thirteen patients (11.4%) had true X chromosome mosaicism (more than 10% of cells have one X chromosome) and 12 (10.5%) had low-level X chromosome mosaicism. The mean age of women with true and low-level mosaicism was 26.0 ± 5.65 years and 35.92 ± 3.87 years, respectively. In the control group the incidence of cells with an abnormal number of X chromosomes was 1–3%. We evaluated the contribution of true and low-level X chromosome mosaicism to POF in phenotypically normal women with sporadic POF by routine G-banding chromosome analysis of at least 50 metaphases. The results have practical implications for genetic counselling and fertility treatment. Although peripheral blood does not reflect the situation in ovarian tissue well, we presume that there are different aetiological causes for true and low-level X chromosome mosaicism.
► AR gene CAG repeat length polymorphism in Croatian women with PCOS was studied. ► Polymorphism was found to be equally distributed between PCOS and healthy controls. ► Polymorphism positively ...correlates with total testosterone levels in PCOS group. ► CAG repeat polymorphism is not associated with hirsutism and acne status. ► Serum androgen levels are not significant predictors of hirsutism and acne status.
Hyperandrogenemia has been the most consistent feature of polycystic ovary syndrome (PCOS). Androgens exert their effects through androgen receptors (ARs). The expansion of the codon CAG trinucleotide repeat polymorphism in exon 1 of the AR gene represents a type of genetic alteration associated with changes in the AR gene function. The purpose of this study was to establish a possible association of the AR gene CAG repeat length polymorphism with PCOS, and its influence on clinical and biochemical androgen traits. Two hundred and fourteen Croatian women with PCOS and 209 healthy control women of reproductive age were enrolled. Phenotypic hyperandrogenism, BMI and waist to hip ratio were recorded. Hormonal profiles, fasting insulin and glucose levels were measured on cycle days 3–5. Genotyping of the CAG repeat polymorphism in the AR gene was performed. We found no significant difference in the mean CAG repeat number between the PCOS patients and controls (22.1±3.4 vs. 21.9±3.2, P=0.286). There was a positive correlation between the CAG repeat length and total testosterone (TT) in the PCOS group (R=0.225, P=0.015). A multiple linear regression model using mean CAG repeat length, BMI, age and HOMA-IR as predictors explained 8.5% (adjusted R2) of the variability in serum TT levels. In this model the CAG repeat polymorphism was found to be a significant predictor of serum TT levels in PCOS patients (P=0.015). The logistic regression analysis revealed that the CAG repeat length is not a significant predictor of hirsutism and acne status (P=0.921 and P=0.437, respectively). The model was adjusted for serum TT, free testosterone, androstendione and DHEAS levels as independent variables, which were also not found to be significant predictors of hirsutism (P=0.687, P=0.194, P=0.675 and P=0.938, respectively) or acne status (P=0.594, P=0.095, P=0.290 and P=0.151, respectively). In conclusion, the AR CAG repeat polymorphism is not a major determinant of PCOS in the Croatian population, but it is a predictor of serum TT level variability in women with PCOS.
Insulin resistance is one of the main characteristics of polycystic ovary syndrome (PCOS) and is probably genetically predisposed. Possible associations of variable nucleotide tandem repeat (VNTR) ...polymorphism of the insulin gene (INS) with insulin resistance and PCOS in Slovene patients were investigated. A total of 117 PCOS patients and 108 age-matched female controls were genotyped for the INS VNTR polymorphism using real-time polymerase chain reaction and measurement of appropriate biochemical and clinical parameters. Serum fasting insulin (I
0) levels and the homeostasis model assessment index were significantly elevated in PCOS patients compared with controls. Class III INS VNTR alleles were significantly more frequent in the PCOS group. The interaction between body mass index and INS VNTR genotype was a significant predictor of serum I
0 level. The interaction of obesity and the III/III INS VNTR genotype might be a risk factor for the development of PCOS.
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