Reproductive Endocrinology and Genetics Unit

West Jerusalem, Israel

Reproductive Endocrinology and Genetics Unit

West Jerusalem, Israel
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Even-Zohar Gross N.,Hadassah Medical Center | Geva-Eldar T.,Hebrew University of Jerusalem | Geva-Eldar T.,Reproductive Endocrinology and Genetics Unit | Pollak Y.,Hebrew University of Jerusalem | And 4 more authors.
European Journal of Medical Genetics | Year: 2017

Introduction: Prenatal diagnosis (PND) raises ethical dilemmas such as the option of termination of pregnancy (TOP) in cases with severe outcome. Prader-Willi Syndrome (PWS), a complex neurogenetic syndrome with high morbidity and mortality throughout life. Recently, a unique prenatal phenotype was reported and TOP becomes a possibility. Objective: To explore factors influencing the attitudes of parents of PWS children toward PND and TOP concerning a hypothetical pregnancy with a PWS fetus. Methods: All 85 parents of individuals with PWS were interviewed regarding their attitudes towards PND and TOP using semi-structured questionnaire. Results: Fifty-seven parents were supportive of invasive PND and 28 of non-invasive tests only; none opposed PND. Thirty eight favored TOP, additional 31 supported TOP under certain conditions such as spiritual advice, 15 were categorically against TOP. Attitudes correlated with religiosity (p < 0.025), mother's education (p < 0.001), mother's work status (p < 0.001), current age of the child with PWS (p < 0.008). Couples had similar attitudes regarding PND and TOP. No correlation was found with gender, genetic subtype and parental age. Conclusions: Most parents of individuals with PWS support PND, however less than half support TOP. Religiosity was the most influential factor. Familial worldview should be taken into account during prenatal counseling. © 2017.

Eldar-Geva T.,Israel Multidisciplinary Prader Willi Syndrome Clinic | Eldar-Geva T.,Reproductive Endocrinology and Genetics Unit | Eldar-Geva T.,Hebrew University of Jerusalem | Hirsch H.J.,Israel Multidisciplinary Prader Willi Syndrome Clinic | And 9 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by an insatiable appetite, dysmorphic features, cognitive and behavioral difficulties, and hypogonadism. The heterogeneous reproductive hormone profiles indicate that some PWS women may have symptoms of hypoestrogenism, while others may potentially be fertile. We describe our experience in the assessment and treatment of hypogonadism in adolescents and adult females with PWS. The study population consisted of 20 PWS females, age ≥16 years (27.3±7.9 years), followed in our clinic (12 deletion, 7 uniparental disomy, 1 imprinting-center defect). General physical examination, pubertal assessment, body mass index (BMI), gynecological examination, ultrasonography, bone densitometry, and hormonal profiles [FSH, LH, inhibin B, estradiol, prolactin, and TSH] were performed. The relevant assessed factors were: FSH and inhibin B, menstrual cycles (oligo/amenorrhea or irregular bleeding), ultrasound findings (endometrial thickness, uterine/ovarian abnormalities), BMI, bone densitometry, and patient/caregivers attitude. We classified seven women with inhibin B >20ng/ml as potentially fertile. Following the assessment of the above factors, we recommended the individual-specific treatment; contraceptive pills, intra-uterine device, estrogen/progesterone replacement, and cyclic progesterone, in 3, 1, 4, and 1 patients, respectively. Four patients did not follow our recommendations due to poor compliance or family refusal. We recommended contraception pills for one 26-year-old woman with inhibin B and FSH levels 53ng/ml and 6.4IU/L; however, she refused treatment, conceived spontaneously and had an abortion. Guidelines for hormonal replacement therapy in PWS need to be tailored individually depending on physical development, hormonal profiles, bone density, and emotional and social needs of each PWS adolescent and adult. © 2013 Wiley Periodicals, Inc.

Hyman J.H.,IVF Unit | Margalioth E.J.,IVF Unit | Rabinowitz R.,Ultrasound Unit | Rabinowitz R.,Hebrew University of Jerusalem | And 8 more authors.
European Journal of Obstetrics Gynecology and Reproductive Biology | Year: 2013

Objective: Dehydroepiandrosterone (DHEA) supplementation for poor responders may improve ovarian response and IVF treatment outcome. This study aimed to determine the mechanism of action of DHEA, and specifically, the stage of folliculogenesis influenced by DHEA. Study design: This is a prospective, self-controlled study of poor responders to IVF treatment, comparing day 3 biochemical (anti-Mullerian hormone (AMH), inhibin B and FSH) and ultrasound (antral follicle count (AFC)) ovarian reserve markers and IVF treatment outcome before and after DHEA supplementation of at least 3 months duration. Results: Thirty-two women were included. Following DHEA, there was a significant increase in AFC (P = 0.0003) without significant changes in the baseline biochemical parameters AMH, inhibin B, or FSH. The enhanced response comprised increased peak estradiol levels (P = 0.0005), number of follicles > 15 mm, oocytes, MII oocytes and embryos (P = 0.004, P = 0.00001, P = 0.0004 and P = 0.0006, respectively) and oocytes number/total FSH dose (P = 0.0009). The proportion of cancelled cycles due to very poor response decreased significantly (P = 0.02). Conclusions: DHEA does not appear to exert influence via recruitment of pre-antral or very small antral follicles (no change in AMH and inhibin B) but rather by rescue from atresia of small antral follicles (increased AFC). © 2013 Elsevier Ireland Ltd. All rights reserved.

Hirsch H.J.,Neuropediatric Unit | Gross I.,Hadassah Hospital | Pollak Y.,Neuropediatric Unit | Pollak Y.,Hebrew University of Jerusalem | And 4 more authors.
PLoS ONE | Year: 2015

Context. Hyperphagia, low resting energy expenditure, and abnormal body composition contribute to severe obesity in Prader Willi syndrome (PWS). Irisin, a circulating myokine, stimulates "browning" of white adipose tissue resulting in increased energy expenditure and improved insulin sensitivity. Irisin has not been previously studied in PWS. Objectives. Compare plasma and salivary irisin in PWS adults and normal controls. Examine the relationship of irisin to insulin sensitivity and plasma lipids. Design and Study Participants A fasting blood sample for glucose, lipids, insulin, leptin, adinopectin, and irisin was obtained from 22 PWS adults and 54 healthy BMI-matched volunteers. Saliva was collected for irisin assay in PWS and controls. Results. Fasting glucose (77±9 vs 83±7mg/dl, p = 0.004), insulin (4.1±2.0 vs 7.9±4.7μU/ml, p<0.001), and triglycerides (74±34 vs 109±71mg/dl, p = 0.007) were lower in PWS than in controls. Insulin resistance (HOMA-IR) was lower (0.79±0.041 vs 1.63±1.02, p<0.001) and insulin sensitivity (QUICKI) was higher (0.41±0.04 vs 0.36±0.03, p<0.001) in PWS. Plasma irisin was similar in both groups, but salivary irisin (64.5±52.0 vs 33.0±12.1ng/ml), plasma leptin (33.5±24.2 vs 19.7±19.3ng/ml) and plasma adinopectin (13.0±10.8 vs 7.6±4.5μg/ml) were significantly greater in PWS (p<0.001). In PWS, plasma irisin showed positive Pearson correlations with total cholesterol (r = 0.58, p = 0.005), LDL-cholesterol (r = 0.59, p = 0.004), and leptin (r = 0.43, p = 0.045). Salivary irisin correlated negatively with HDL-cholesterol (r = -0.50, p = 0.043) and positively with LDL-cholesterol (r = 0.51, p = 0.037) and triglycerides (r = 0.50, p = 0.041). Conclusions. Salivary irisin was markedly elevated in PWS although plasma irisin was similar to levels in controls. Significant associations with plasma lipids suggest that irisin may contribute to the metabolic phenotype of PWS. © 2015 Hirsch et al.

Gross-Tsur V.,Shaare Zedek Medical Center | Gross-Tsur V.,Neuropediatric Unit | Gross-Tsur V.,Hebrew University of Jerusalem | Hirsch H.J.,Shaare Zedek Medical Center | And 4 more authors.
Reproductive Biology and Endocrinology | Year: 2012

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 (<10 pg/ml); Group B: central hypogonadism (FSH <0.5 IU/l, INB <10 pg/ml); Group C: partial gonadal & central dysfunction (FSH 1.5-15 IU/l, INB >20 pg/ml); Group D: mild central and severe gonadal dysfunction (FSH 1.5-15 IU/l, INB < 10 pg/ml.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. © 2012 Gross-Tsur et al.; licensee BioMed Central Ltd.

Gross N.,Reproductive Endocrinology and Genetics Unit | Gross N.,Ultrasound Unit | Gross N.,Hebrew University of Jerusalem | Rabinowitz R.,Ultrasound Unit | And 6 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

The aim of this study was to characterize the fetal phenotype of a cohort of individuals with confirmed diagnoses of Prader-Willi syndrome (PWS), a severe multi-system genetic disorder, diagnosed by a specific methylation test. We interviewed mothers of 106 individuals with PWS to obtain information about the pregnancy of their affected child. For 47 pregnancies of children younger than 10 years, we also reviewed the obstetric ultrasound and detailed obstetric history from medical records. We compared the PWS pregnancies with those of the sibling closest in age and with the general population. McNemars, Chi-square and Fisher exact tests were used for statistical analyses. Decreased fetal movements, small for gestational age (SGA), asymmetrical intrauterine growth (increased head/abdomen circumferences ratio) and polyhydramnios were found in 88%, 65%, 43%, and 34%, respectively (P<0.001 vs. siblings and P<0.0001 vs. the general population for all measurements). No severe morphological abnormalities were found. A combination of 2, 3, and 4 abnormalities was found in 27%, 29%, and 24% of pregnancies, respectively. Fourteen out of 15 umbilical artery Doppler studies were within the normal range (93%). The rare combination of asymmetrical intrauterine growth and polyhydramnios was found in 34% of PWS pregnancies (P<0.0001 vs. the general population). Prenatal genetic screening for PWS by methylation testing is indicated when any combination of polyhydramnios, SGA or asymmetric intrauterine growth, with normal Doppler studies is present, particularly when asymmetrical intrauterine growth and polyhydramnios coexist. © 2014 Wiley Periodicals, Inc.

Srebnik N.,Reproductive Endocrinology and Genetics Unit | Srebnik N.,Hebrew University of Jerusalem | Margalioth E.J.,Reproductive Endocrinology and Genetics Unit | Rabinowitz R.,Hebrew University of Jerusalem | And 11 more authors.
Reproductive BioMedicine Online | Year: 2014

Myotonic dystrophy (DM) is the most common form of muscular dystrophy in adults. There are conflicting reports about its effect on female fertility. This study investigated ovarian reserve and IVF-preimplantation genetic diagnosis (PGD) outcome in women with DM1. A total of 21 women undergoing PGD for DM1 were compared with 21 age- and body mass index-matched women undergoing PGD for other diseases. Ovarian reserve markers, response to stimulation, embryo quality and clinical pregnancy and live birth rates were compared. Day-3 FSH concentration was higher, while anti-Müllerian hormone concentration and antral follicle count were lower in the DM1 group (median, range: 6.9 (1.8-11.3) versus 5.7 (1.5-10.7) IU/l; 0.9 (0.17-5.96) versus 2.68 (0.5-9.1) ng/ml; and 13 (0-63) versus 23 (8-40) follicles, respectively, all P < 0.05). Total FSH dose was higher (5200 versus 2250 IU, P = 0.004), while the numbers of oocytes retrieved (10 versus 16, P < 0.04) and metaphase-II oocytes (9 versus 12, P < 0.03) were lower in the DM1 group. The number of cycles with top-quality embryos and the clinical pregnancy rate were lower in the DM1 group. In conclusion, there is evidence of diminished ovarian reserve and less favourable IVF-PGD outcome in women with DM1. Myotonic Dystrophy (DM) is the most common form of muscular dystrophy in adults. There is evidence of subfertility in males affected with the disease but conflicting reports about the effect of the disease on female fertility. The aim of our study was to investigate ovarian reserve and IVF-PGD results in women with DM. Twenty-one women undergoing preimplantation genetic diagnosis (PGD) treatment for DM were compared to 21 age- and BMI matched women undergoing PGD treatment for other diseases. The two groups were compared for antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) levels (the best known markers of ovarian reserve and fertility potential), ovarian response, embryo quality and pregnancy and live birth rates. AFC and the AMH levels were statistically significant lower in the DM group. Total medication dose needed for ovarian stimulation was higher, the number of oocytes and mature oocytes retrieved, and the number of cycles with top quality embryos were lower in the DM group compared to the controls. In conclusion, there is evidence of diminished ovarian reserve, and less favorable IVF-PGD outcome in women with DM. Therefore, we recommend advising these women about the possibility of early decreasing ovarian function in order to prevent any delay in reproductive planning. © 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

PubMed | Hebrew University of Jerusalem, Reproductive Endocrinology and Genetics Unit, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Neuropediatric Unit and 3 more.
Type: Journal Article | Journal: Molecular metabolism | Year: 2016

Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid(eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CBWe studied eCB tone in individuals with PWS and in the Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB tone, manifested by increased eCBs and upregulated CBDysregulation of the eCB/CB

Sacks G.C.,Medical Genetics Institute | Sacks G.C.,Neuropsychology Unit | Sacks G.C.,Hebrew University of Jerusalem | Altarescu G.,Medical Genetics Institute | And 8 more authors.
Child Neuropsychology | Year: 2016

The purpose of this pilot study was to evaluate developmental neuropsychological profiles of 4-to 5-year-old children born after Preimplantation Genetic Diagnosis (PGD). Twenty-seven participants received a neurological examination and a battery of neuropsychological assessments including Wechsler Preschool & Primary Scale of Intelligence-Third Edition (WPPSI-III; cognitive development), Preschool Language Scale, Fourth Edition (PLS-4; language development), Wide Range Assessment of Visual Motor Abilities (visual motor abilities), Childhood Autism Rating Scales II (a screening test for autistic spectrum disorders), and the Miles ABC Test (ocular dominance). Parental questionnaires included the Behavior Rating Inventory of Executive Function Preschool Version (BRIEF-P; executive function), Child Behavior Checklist (CBCL) and the Carey Temperament Scales Behavioral Style Questionnaire (socioemotional development and temperament), and the Vineland Adaptive Behavior Scales, Interview Edition, Second Edition (general adaptive behavior). Subjects tests results were compared to each tests norms. Children born after PGD demonstrated scores within the normal or above-normal ranges for all developmental outcomes (mean ± SD): WPPSI-III-VIQ 107.4 ± 14.4 (p =.013), PLS-4-Total 113.2 ± 12.4, p <.001), CBCL-Total 41.1 ± 8.6 (p <.001), BRIEF-P-Global Executive Composite 44.8 ± 9.5 (p =.009). Twelve (44%) of the PGD children had a significant difference between their VIQ and PIQ scores (compared to 27% in the general population). One subject was found to show possible signs of autistic spectrum disorder, although a family history of autism was noted. In conclusion, in this pilot study, children assessed at age 4-5 years and conceived after PGD displayed developmental neuropsychological outcomes within normal limits as compared to their chronologic peers. A larger study is needed to evaluate and follow the neuropsychological development of children born after PGD. © 2015 Taylor and Francis.

Eldar-Geva T.,Reproductive Endocrinology and Genetics Unit | Eldar-Geva T.,Hebrew University of Jerusalem | Srebnik N.,Reproductive Endocrinology and Genetics Unit | Srebnik N.,Hebrew University of Jerusalem | And 10 more authors.
Fertility and Sterility | Year: 2014

Objective: To examine whether embryo biopsy for preimplantation genetic diagnosis (PGD) influences neonatal outcomes.Design: Prospective follow-up cohort.Setting: Tertiary university-affiliated medical center.Patient(s): 242 children born after PGD, 242 children born after intracytoplasmic sperm injection (ICSI) (158 singletons and 42 twins pairs in each group), and 733 children born after a spontaneous conception (SC) (493 singletons, 120 twins pairs), matched for maternal age, parity, and body mass index.Intervention(s): None.Main Outcome Measure(s): Gestational age, birth weight, prematurity (<37 and <34 weeks), low birth weight (<2,500 g, very low birth weight, <1,500 g), and intrauterine growth restriction (<10th percentile for gestational age).Result(s): For singletons, the mean birth weight was higher after SC compared with ICSI but not compared with PGD. Mean gestational ages were lower after PGD and ICSI compared with SC. The low birth weight and intrauterine growth restriction rates were 4.4%, 12.0%, and 5.7% and 5.1%, 9.5%, and 5.5% for PGD, ICSI, and SC, respectively. Similar results were found when controlled for the number of embryos transferred and cryopreservation. The results for twins exhibited similar but less statistically significant trends. Polar body and blastomere biopsies provided similar outcomes.Conclusion(s): Embryo biopsy itself did not cause intrauterine growth restriction or low birth weight compared with SC, despite lower gestational ages with PGD. The worsened outcomes in ICSI compared with PGD pregnancies may be due to the infertility itself. © 2014 American Society for Reproductive Medicine.

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