The FSH-inhibin axis in prader-willi syndrome: heterogeneity of gonadal dysfunction

Abstract Background We characterized the spectrum and etiology of hypogonadism in a cohort of Prader-Willi syndrome (PWS) adolescents and adults. Methods Reproductive hormonal profiles and physical examination were performed on 19 males and 16 females ages 16–34 years with PWS. Gonadotropins, sex-steroids, inhibin B (INB) and anti-Mullerian hormone (AMH) were measured. We defined 4 groups according to the relative contribution of central and gonadal dysfunction based on FSH and INB levels: Group A: primary hypogonadism (FSH >15 IU/l and undetectable INB (20 pg/ml); Group D: mild central and severe gonadal dysfunction (FSH 1.5–15 IU/l, INB  Results There were 10, 8, 9 and 8 individuals in Groups A-D respectively; significantly more males in group A (9, 4, 4 and 2; P = 0.04). Significant differences between the groups were found in mean testosterone (P = 0.04), AMH (P = 0.003) and pubic hair (P = 0.04) in males and mean LH (P = 0.003) and breast development (P = 0.04) in females. Mean age, height, weight, BMI and the distribution of genetic subtypes were similar within the groups. Conclusions Analysis of FSH and inhibin B revealed four distinct phenotypes ranging from primary gonadal to central hypogonadism. Primary gonadal dysfunction was common, while severe gonadotropin deficiency was rare. Longitudinal studies are needed to verify whether the individual phenotypes are consistent.</p

Global Characterization of X Chromosome Inactivation in Human Pluripotent Stem Cells

Summary: Dosage compensation of sex-chromosome gene expression between male and female mammals is achieved via X chromosome inactivation (XCI) by employing epigenetic modifications to randomly silence one X chromosome during early embryogenesis. Human pluripotent stem cells (hPSCs) were reported to present various states of XCI that differ according to the expression of the long non-coding RNA XIST and the degree of X chromosome silencing. To obtain a comprehensive perspective on XCI in female hPSCs, we performed a large-scale analysis characterizing different XCI parameters in more than 700 RNA high-throughput sequencing samples. Our findings suggest differences in XCI status between most published samples of embryonic stem cells (ESCs) and induced PSCs (iPSCs). While the majority of iPSC lines maintain an inactive X chromosome, ESC lines tend to silence the expression of XIST and upregulate distal chromosomal regions. Our study highlights significant epigenetic heterogeneity within hPSCs, which may bear implications for their use in research and regenerative therapy. : Bar et al. perform a large-scale analysis of X chromosome inactivation (XCI) in over 700 samples of human pluripotent stem cells (PSCs). Erosion of XCI involves stable silencing of XIST and partial overexpression of distal X-linked genes and is prevalent in embryonic stem cells, but not in most induced PSCs. Keywords: X inactivation, human embryonic stem cells, human induced pluripotent stem cells, XIS

Ethics and regulation of inter-country medically assisted reproduction:A call for action

The proliferation of medically assisted reproduction (MAR) for the treatment of infertility has brought benefit to many individuals around the world. But infertility and its treatment continue to be a cause of suffering, and over the past decade, there has been a steady growth in a new global market of inter-country medically assisted reproduction (IMAR) involving 'third-party' individuals acting as surrogate mothers and gamete donors in reproductive collaborations for the benefit of other individuals and couples who wish to have children. At the same time there is evidence of a double standard of care for third-party women involved in IMAR, violations of human rights of children and women, and extreme abuses that are tantamount to reproductive trafficking. This paper is the report of an inter-disciplinary working group of experts who convened in Israel to discuss the complex issues of IMAR. In Israel too IMAR practices have grown rapidly in recent years, mainly because of restrictions on access to domestic surrogacy for same sex couples and a chronically insufficient supply of egg cells for the treatment of couples and singles in need. Drawing upon local expertise, the paper describes documented practices that are harmful, suggests principles of good practice based on an ethic of care, and calls for action at the international, national and professional levels to establish a human rights based system of international governance for IMAR based on three regulatory models: public health monitoring, inter-country adoption, and trafficking in human beings, organs and tissues.</p

Anesthetic management for oocyte retrieval: An exploratory analysis comparing outcome in in vitro fertilization cycles with and without pre-implantation genetic diagnosis

Purpose: To date, there has been no comparison of outcomes in women undergoing anesthesia for in vitro fertilization (IVF) oocyte retrieval for the purpose of pre-implantation genetic diagnosis (PGD) because of their or their partner′s genetic disease relative to the outcome in women requiring IVF because of fertility issues. Materials and Methods: A prospective observational study, wherein all demographic and anesthetic management data were collected from IVF and PGD units′ records for a 6-month period. Descriptive analyses and parametric tests were employed. Results: There were 307 cases IVF and 76 cases PGD: most (97.4% and 99.7%, respectively) received general anesthesia with propofol and fentanyl ± dipyrone (90.5% and 93.3%, respectively) with no adverse effects. The only statistically significant difference between IVF and PGD groups that was potentially clinically significant was post-procedure recovery time (23.0 ± 20.4 vs. 29.4 ± 35.8 min, respectively; P < 0.0001), but is explainable as greater caution by Anesthesiologists for higher-risk PGD cases having autosomal dominant diseases that may impact anesthesia management (myotonic dystrophy, neurofibromatosis, Marfan′s); two of these cases also recovered in the general post-anesthesia care unit, as a precaution for early diagnosis and treatment of potential post-procedural complication. Conclusions: Results of this first-ever survey of anesthesia for PGD compared with IVF cases imply that propofol-and-fentanyl-based anesthesia is safe and can be recommended, bearing in mind that with patients who have autosomal dominant diseases impacting anesthetic management it is prudent to be more cautious post-recovery

Preconception Screening for Cytomegalovirus: An Effective Preventive Approach

Congenital cytomegalovirus (CMV) is the leading infectious cause of sensorineural hearing loss and delayed psychomotor development. Viral transmission to the fetus is far more likely to occur following a primary than a secondary maternal infection. Primary prevention seems to be the best means to reduce the burden of congenital CMV due to the lack of treatment options during pregnancy. We evaluated this approach on a cohort of 500 women planning pregnancy who attended our fertility clinic. Of the 444 who underwent CMV screening, 18 (4.1%) had positive IgM serology for CMV; of these, IgG avidity was high in 12 (remote infection) and low in 6 (recent infection). The latter were advised to delay pregnancy. All women who were seroimmune for CMV (366/444, 82.4%), including the 12 with remote infection, continued fertility treatment. The remaining patients (72/444, 16.2%), who were not immune to CMV at the initial screen, were advised to minimize CMV exposure by improving personal hygiene and to continue fertility treatment. None of the 69/72 (95.8%) women who were followed for one year were infected with CMV. Cytomegalovirus testing and counselling at preconception seemed effective in reducing CMV exposure in pregnancy

DMPK hypermethylation in sperm cells of myotonic dystrophy type 1 patients

International audienceMyotonic dystrophy type 1 (DM1) is an autosomal dominant muscular dystrophy that results from a CTG expansion (50–4000 copies) in the 3′ UTR of the DMPK gene. The disease is classified into four or five somewhat overlapping forms, which incompletely correlate with expansion size in somatic cells of patients. With rare exception, it is affected mothers who transmit the congenital (CDM1) and most severe form of the disease. Why CDM1 is hardly ever transmitted by fathers remains unknown. One model to explain the almost exclusive transmission of CDM1 by affected mothers suggests a selection against hypermethylated large expansions in the germline of male patients. By assessing DNA methylation upstream to the CTG expansion in motile sperm cells of four DM1 patients, together with availability of human embryonic stem cell (hESCs) lines with paternally inherited hypermethylated expansions, we exclude the possibility that DMPK hypermethylation leads to selection against viable sperm cells (as indicated by motility) in DM1 patients

Pearson correlations of plasma irisin with clinical and biochemical parameters.

<p>Pearson correlations of plasma irisin with clinical and laboratory parameters in PWS patients and non-PWS controls. Values for which the correlations are statistically significant (p < 0.05) are shown in bold font.</p><p>Pearson correlations of plasma irisin with clinical and biochemical parameters.</p

Clinical and biochemical characteristics in PWS and normal controls according to BMI status (obese/overweight vs normal BMI).

<p>Mean±SD values for clinical and laboratory parameters for overweight PWS patients (BMI > 25 kg/m²) compared with overweight control volunteers, anda for PWS patients whose BMI was less than 25 kg/m² compared with lean control participants. Values which are significantly different between the two groups appear in bold. Differences among the four groups were analysed using a 2 by 2 ANOVA, followed by post-hoc Tukey tests. CRP levels were not normally distributed and were analysed using Kruskal-Wallis and Mann-Whitney tests. Values which differ significantly between the groups are shown in bold font.</p><p>Clinical and biochemical characteristics in PWS and normal controls according to BMI status (obese/overweight vs normal BMI).</p