<b><i>Objective:</i></b> The study aimed to assess whether sub-endometria... more <b><i>Objective:</i></b> The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramuscular (IM) progesterone. <b><i>Design:</i></b> This is a randomized clinical trial. Patients assigned to a medicated day 5 frozen embryo transfer (FET) were randomly allocated to "vaginal progesterone" or "IM progesterone": patients randomized to the vaginal arm were treated with 200 mg micronized progesterone 3 times daily while patients randomized into the IM progesterone arm were treated with a single daily injection of 50 mg progesterone in oil. The main outcome measure was the number of sub-endometrial contractions (waves) per minute 1 day before a blastocyst embryo transfer. <b><i>Results:</i></b> Thirty-four patients were enrolled. The progesterone serum concentration was significantly higher in patients using the IM progesterone (85.2 ± 50.1 vs. 30.3 ± 11.2 nmol/L, respectively) but this did not translate into a lower sub-endometrial contractility (2.4 ± 4.8 vs. 1.4 ± 1.1 contraction/min, respectively). Clinical pregnancy rates were comparable between groups. The number of sub-endometrial waves was significantly lower among pregnant patients (<i>p</i> = 0.02). <b><i>Conclusions:</i></b> The use of IM progesterone in medicated FET cycles does not reduce the sub-endometrial activity compared to vaginal progesterone administration. Our data support a poor clinical pregnancy outcome with high wave activity, regardless of the progesterone mode.
Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regress... more Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regression of male fetal Mullerian ducts. During puberty, AMH is downregulated by intratesticular testosterone. In females, AMH is secreted from granulosa cells of immature ovarian follicles from late prenatal life until menopause; serum concentration is 5-20 times lower in females than in males through lifetime. In boys, AMH determination is useful in the clinical setting as a marker of Sertoli cell function. Serum AMH is low in infants with hypogonadotrophic hypogonadism (and increases with FSH treatment), in patients with primary hypogonadism from early postnatal life and in Klinefelter syndrome from midpuberty. In boys with nonpalpable gonads, AMH determination is useful to distinguish between cryptorchidism and anorchism, as well as differentiating the dysgenetic causes of disorders of sexual development from those due to defective androgen synthesis or action. AMH can be used as a marker of sertoli/granulosa cell tumors and primary ovarian insufficiency in girls with delayed puberty, Turner Syndrome and after treatment with gonadotoxic agents.
Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant an... more Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant aneuploidy (9M in mouse), heterochromatin histone marks are lost, and oocyte maturation is impaired. This loss occurs in both constitutive and facultative heterochromatin marks but not in euchromatic active marks. We show that heterochromatin loss with age also occurs in human prophase I‐arrested oocytes. Moreover, heterochromatin loss is accompanied in mouse oocytes by an increase in RNA processing and associated with an elevation in L1 and IAP retrotransposon expression and in DNA damage and DNA repair proteins nuclear localization. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and oocyte maturation defects. Inhibiting retrotransposon reverse‐transcriptase through azidothymidine (AZT) treatment in older oocytes partially rescues their maturation defects and activity of the DNA repair machinery. Moreover, activating the heterochromatin machinery via treatment with the SIRT1 activating molecule SRT‐1720, or overexpression of Sirt1 or Ezh2 via plasmid electroporation into older oocytes causes an upregulation in constitutive heterochromatin, downregulation of retrotransposon expression, and elevated maturation rates. Collectively, our work demonstrates a significant process in oocyte aging, characterized by the loss of heterochromatin‐associated chromatin marks and activation of specific retrotransposons, which cause DNA damage and impair oocyte maturation.
Journal of Pediatric Gastroenterology and Nutrition, Mar 1, 2009
Objectives: Most patients with cystic fibrosis (CF) have pancreatic insufficiency; however, 15% o... more Objectives: Most patients with cystic fibrosis (CF) have pancreatic insufficiency; however, 15% of the patients are pancreatic sufficient (PS). Several laboratory tests have been developed to distinguish between pancreatic insufficiency and PS. The gold standard to determine pancreatic function apart from direct pancreatic stimulation test is the 72-hour fecal fat excretion, expressed as coefficient of fat absorption (CFA). The aim was to test the correlation between 2 other tests, fecal elastase-1 and serum immunoreactive trypsinogen (IRT), as compared with fecal fat excretion. Patients and Methods: 21 patients with CF-PS performed the 3 tests of fecal fat excretion, fecal elastase-1, and IRT. Correlation between the tests was evaluated by the k statistics test, sensitivity and specificity, and positive and negative predictive values. Results: CFA was abnormal in 5 patients, elastase was <200 mg/g in 4 patients, and IRT was <20 ng/mL in 2 patients. The correlation between CFA and IRT was negative (k ¼ À0.154), and between CFA and fecal elastase-1 was poor (k ¼ 0.213). The sensitivity, specificity, and positive and negative predictive values of IRT versus CFA were 0%, 88%, 0%, and 78%, and for fecal elastase-1 were 40%, 81%, 40%, and 81%, respectively. Conclusions: In CF-PS, poor correlation was found between IRT, fecal elastase-1, and CFA, therefore neither fecal elastase-1 in the stool nor IRT in the serum reaches the sensitivity or the specificity of the fecal fat excretion. Thus, fecal fat excretion is required in patients with CF for evaluation of pancreatic function. JPGN 48:306-310, 2009.
Objective: To describe prostanoid DP receptor (PTGDR) variants in women with preterm births who a... more Objective: To describe prostanoid DP receptor (PTGDR) variants in women with preterm births who admitted to coital activity (CA) within 24 h of labor. Study Design: To achieve >80% statistical power, a pilot case-control study compared 24 premature births from mothers with CA (Group 1), 30 mothers of premature infants who did not have CA (Group 2 non-coital activity) and 95 non-coital activity mothers with term births (Group 3 controls). Four functional PTDGR single nucleotide polymorphisms (SNPs) were evaluated: T-549C, C-441/T, T-197C and G þ 1044A. PHASE 2.0.2 and SAS 9.2 were used for analysis. Result: All SNPs were in Hardy-Weinberg equilibrium in controls. The C-441/T genotype frequency was significantly increased among Group 1 women relative to Group 2 and 3 women (odds ratio (OR): 30.1, 95% confidence interval (CI) 6.9-191 and 25.7 95%CI 25.7-not computible, respectively). Of the possible haplotypes among the groups, the TCTG haplotype (T-549C, C-441/T, T-197C and G þ 1044A) was significantly more frequent in Group 1 women compared with the control groups (OR 53.4, 95%CI 10.3-554.8). Conclusions: A differential genomic pattern of PTGDR polymorphisms was identified in a subset of mothers which was associated with an increased risk of post-coital preterm birth.
What are the success rates of social oocyte cryopreservation (SOC) at advanced age? In this study... more What are the success rates of social oocyte cryopreservation (SOC) at advanced age? In this study, one in four women who underwent SOC above age 35 had a delivery. While SOC is gaining popularity, reports on delivery rates are limited due to low utilization rates. Retrospective data collection of all woman who underwent SOC between 2011–2018, and presented for treatment using cryopreserved oocytes until January 2021. Participants/materials, setting, methods: Review of patient records (including both IVF and antenatal/postnatal) and laboratory data in a university affiliated hospital-based IVF unit. Main results and the role of chance: A total of 448 women underwent SOC during 2011–2018. 50 (11.2%) women returned to use these oocytes until the end of January 2021. Women who returned to use their oocytes underwent cryopreservation at mean age of 38.2±2.2. 46 (92%) of participants were above 35 at time of cryopreservation. Number of oocytes cryopreserved was 11.3±9.7. Mean time from cr...
Journal of Osteoporosis and Physical Activity, 2017
Introduction: Prader-Willi syndrome (PWS (is caused by lack of paternally expressed imprinted gen... more Introduction: Prader-Willi syndrome (PWS (is caused by lack of paternally expressed imprinted genes at chromosome 15q11.2-q13. Diminished (BMD) and osteoporosis are common in PWS. The purpose of this study was to determine whether polymorphisms in genes previously shown to correlate with bone mineral density (BMD), might explain the variable expression of abnormal BMD in PWS. Material and methods: Blood samples were collected from 96 PWS individuals aged 3.5-47.9 (median 14.4) years. DNA samples were tested for 12 polymorphisms in 8 candidate genes: interleukin-1 (IL1-alfa, IL1-beta and IL1RN), CYP1A1, Low Density Lipoprotein Receptor-Related Protein 5 (LRP5), vitamin D receptor (VDR), RANK and RANKL. All patients underwent BMD measurements at the femoral neck and lumbar spine using a hologic dual energy x-ray absorptiometry (DXA) machine. Results: Abnormal BMD was defined as Z-score <-1.5. Severe reduced BMD as Z-score <-2.5. 67 subjects (70%) had abnormal BMD (youngest 3.7 y...
Gynecologic and obstetric investigation, Jan 13, 2017
The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramus... more The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramuscular (IM) progesterone. This is a randomized clinical trial. Patients assigned to a medicated day 5 frozen embryo transfer (FET) were randomly allocated to "vaginal progesterone" or "IM progesterone": patients randomized to the vaginal arm were treated with 200 mg micronized progesterone 3 times daily while patients randomized into the IM progesterone arm were treated with a single daily injection of 50 mg progesterone in oil. The main outcome measure was the number of sub-endometrial contractions (waves) per minute 1 day before a blastocyst embryo transfer. Thirty-four patients were enrolled. The progesterone serum concentration was significantly higher in patients using the IM progesterone (85.2 ± 50.1 vs. 30.3 ± 11.2 nmol/L, respectively) but this did not translate into a lower sub-endometrial contractility (2.4 ± 4.8 vs. 1.4 ± 1.1 contraction/min, respectively). ...
Research Question We sought to determine why women facing poor prognoses for success in Assisted ... more Research Question We sought to determine why women facing poor prognoses for success in Assisted Reproductive Technologies (ART) choose to pursue treatments using their own eggs, despite receiving information that their chances for success are very low. Design A cross-sectional study based on an anonymous questionnaire distributed to female patients aged 43-45, undergoing ART using their own oocytes, at six public outpatient fertility clinics and three public in-hospital IVF units in Israel during the years 2015-2016. The main outcome measure was personal estimation of chance to achieve a live birth following the current ART treatment cycle and the cumulative estimated rate following all the treatment cycles the patient intended to undergo. Results Response rate was 70.0%. Mean age of participants was 43.8±0.7 years. Participants estimated their delivery rates following the next ART treatment cycle at 49.0 ± 31.8 % and their cumulative delivery rates after all the ART treatments they would undergo at 57.7 ± 36.2%. This is significantly higher than the predicted success rates of 5% and 15%, respectively, that are based on national register data. Nearly half rated themselves as having a better than the average chance of conception (47.3%). Conclusion Women do not pursue futile treatments because they lack information. Despite being informed of the low success rates of conception using ART treatments, many advanced maternal age patients have unrealistically high expectations from ART, essentially ignoring their estimated prognosis when deciding on treatment continuation. Future work should examine the psychological reasons behind continuing futile fertility treatments.
Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant an... more Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant aneuploidy (9M in mouse), heterochromatin histone marks are lost, and oocyte maturation is impaired. This loss occurs in both constitutive and facultative heterochromatin marks but not in euchromatic active marks. We show that heterochromatin loss with age also occurs in human prophase I‐arrested oocytes. Moreover, heterochromatin loss is accompanied in mouse oocytes by an increase in RNA processing and associated with an elevation in L1 and IAP retrotransposon expression and in DNA damage and DNA repair proteins nuclear localization. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and oocyte maturation defects. Inhibiting retrotransposon reverse‐transcriptase through azidothymidine (AZT) treatment in older oocytes partially rescues their maturation defects and activity of the DNA repair machinery. Moreover, activating the heterochromatin machinery via treatment with the SIRT1 activating molecule SRT‐1720, or overexpression of Sirt1 or Ezh2 via plasmid electroporation into older oocytes causes an upregulation in constitutive heterochromatin, downregulation of retrotransposon expression, and elevated maturation rates. Collectively, our work demonstrates a significant process in oocyte aging, characterized by the loss of heterochromatin‐associated chromatin marks and activation of specific retrotransposons, which cause DNA damage and impair oocyte maturation.
Mammalian oocyte quality reduces with female age. A well-studied aspect of this deterioration is ... more Mammalian oocyte quality reduces with female age. A well-studied aspect of this deterioration is an age-associated rise in oocyte aneuploidy. We show that prior to the occurrence of significant aneuploidy (at the age of 9 months in mouse females), epigenetic changes occur and impact oocyte quality and maturation ability. At this age- we observe a reduction in heterochromatin marks in mouse oocytes. This decrease is apparent in both constitutive heterochromatin and facultative heterochromatin marks but is absent in active euchromatic marks which remain constant. A decrease of heterochromatin marks with age is also observed in human GV oocytes from IVF treatments. Heterochromatin loss with age is associated with an elevation in retrotransposon RNA transcription and processing, an elevation in retrotransposon protein expression, elevation in DNA repair proteins nuclear localization and oocyte maturation defects. Artificial inhibition of the heterochromatin machinery in young oocytes ca...
Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regress... more Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regression of male fetal Mullerian ducts. During puberty, AMH is downregulated by intratesticular testosterone. In females, AMH is secreted from granulosa cells of immature ovarian follicles from late prenatal life until menopause; serum concentration is 5-20 times lower in females than in males through lifetime. In boys, AMH determination is useful in the clinical setting as a marker of Sertoli cell function. Serum AMH is low in infants with hypogonadotrophic hypogonadism (and increases with FSH treatment), in patients with primary hypogonadism from early postnatal life and in Klinefelter syndrome from midpuberty. In boys with nonpalpable gonads, AMH determination is useful to distinguish between cryptorchidism and anorchism, as well as differentiating the dysgenetic causes of disorders of sexual development from those due to defective androgen synthesis or action. AMH can be used as a marker ...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2014
To determine whether the decrease in AMH levels during ovarian hyperstimulation for IVF occurs in... more To determine whether the decrease in AMH levels during ovarian hyperstimulation for IVF occurs in patients with polycystic ovary syndrome (PCOS) and patients with low ovarian reserve (LOR), as in normal cycling women.
Research Question We sought to determine why women facing poor prognoses for success in Assisted ... more Research Question We sought to determine why women facing poor prognoses for success in Assisted Reproductive Technologies (ART) choose to pursue treatments using their own eggs, despite receiving information that their chances for success are very low. Design A cross-sectional study based on an anonymous questionnaire distributed to female patients aged 43-45, undergoing ART using their own oocytes, at six public outpatient fertility clinics and three public in-hospital IVF units in Israel during the years 2015-2016. The main outcome measure was personal estimation of chance to achieve a live birth following the current ART treatment cycle and the cumulative estimated rate following all the treatment cycles the patient intended to undergo. Results Response rate was 70.0%. Mean age of participants was 43.8±0.7 years. Participants estimated their delivery rates following the next ART treatment cycle at 49.0 ± 31.8 % and their cumulative delivery rates after all the ART treatments they would undergo at 57.7 ± 36.2%. This is significantly higher than the predicted success rates of 5% and 15%, respectively, that are based on national register data. Nearly half rated themselves as having a better than the average chance of conception (47.3%). Conclusion Women do not pursue futile treatments because they lack information. Despite being informed of the low success rates of conception using ART treatments, many advanced maternal age patients have unrealistically high expectations from ART, essentially ignoring their estimated prognosis when deciding on treatment continuation. Future work should examine the psychological reasons behind continuing futile fertility treatments.
<b><i>Objective:</i></b> The study aimed to assess whether sub-endometria... more <b><i>Objective:</i></b> The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramuscular (IM) progesterone. <b><i>Design:</i></b> This is a randomized clinical trial. Patients assigned to a medicated day 5 frozen embryo transfer (FET) were randomly allocated to "vaginal progesterone" or "IM progesterone": patients randomized to the vaginal arm were treated with 200 mg micronized progesterone 3 times daily while patients randomized into the IM progesterone arm were treated with a single daily injection of 50 mg progesterone in oil. The main outcome measure was the number of sub-endometrial contractions (waves) per minute 1 day before a blastocyst embryo transfer. <b><i>Results:</i></b> Thirty-four patients were enrolled. The progesterone serum concentration was significantly higher in patients using the IM progesterone (85.2 ± 50.1 vs. 30.3 ± 11.2 nmol/L, respectively) but this did not translate into a lower sub-endometrial contractility (2.4 ± 4.8 vs. 1.4 ± 1.1 contraction/min, respectively). Clinical pregnancy rates were comparable between groups. The number of sub-endometrial waves was significantly lower among pregnant patients (<i>p</i> = 0.02). <b><i>Conclusions:</i></b> The use of IM progesterone in medicated FET cycles does not reduce the sub-endometrial activity compared to vaginal progesterone administration. Our data support a poor clinical pregnancy outcome with high wave activity, regardless of the progesterone mode.
Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regress... more Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regression of male fetal Mullerian ducts. During puberty, AMH is downregulated by intratesticular testosterone. In females, AMH is secreted from granulosa cells of immature ovarian follicles from late prenatal life until menopause; serum concentration is 5-20 times lower in females than in males through lifetime. In boys, AMH determination is useful in the clinical setting as a marker of Sertoli cell function. Serum AMH is low in infants with hypogonadotrophic hypogonadism (and increases with FSH treatment), in patients with primary hypogonadism from early postnatal life and in Klinefelter syndrome from midpuberty. In boys with nonpalpable gonads, AMH determination is useful to distinguish between cryptorchidism and anorchism, as well as differentiating the dysgenetic causes of disorders of sexual development from those due to defective androgen synthesis or action. AMH can be used as a marker of sertoli/granulosa cell tumors and primary ovarian insufficiency in girls with delayed puberty, Turner Syndrome and after treatment with gonadotoxic agents.
Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant an... more Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant aneuploidy (9M in mouse), heterochromatin histone marks are lost, and oocyte maturation is impaired. This loss occurs in both constitutive and facultative heterochromatin marks but not in euchromatic active marks. We show that heterochromatin loss with age also occurs in human prophase I‐arrested oocytes. Moreover, heterochromatin loss is accompanied in mouse oocytes by an increase in RNA processing and associated with an elevation in L1 and IAP retrotransposon expression and in DNA damage and DNA repair proteins nuclear localization. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and oocyte maturation defects. Inhibiting retrotransposon reverse‐transcriptase through azidothymidine (AZT) treatment in older oocytes partially rescues their maturation defects and activity of the DNA repair machinery. Moreover, activating the heterochromatin machinery via treatment with the SIRT1 activating molecule SRT‐1720, or overexpression of Sirt1 or Ezh2 via plasmid electroporation into older oocytes causes an upregulation in constitutive heterochromatin, downregulation of retrotransposon expression, and elevated maturation rates. Collectively, our work demonstrates a significant process in oocyte aging, characterized by the loss of heterochromatin‐associated chromatin marks and activation of specific retrotransposons, which cause DNA damage and impair oocyte maturation.
Journal of Pediatric Gastroenterology and Nutrition, Mar 1, 2009
Objectives: Most patients with cystic fibrosis (CF) have pancreatic insufficiency; however, 15% o... more Objectives: Most patients with cystic fibrosis (CF) have pancreatic insufficiency; however, 15% of the patients are pancreatic sufficient (PS). Several laboratory tests have been developed to distinguish between pancreatic insufficiency and PS. The gold standard to determine pancreatic function apart from direct pancreatic stimulation test is the 72-hour fecal fat excretion, expressed as coefficient of fat absorption (CFA). The aim was to test the correlation between 2 other tests, fecal elastase-1 and serum immunoreactive trypsinogen (IRT), as compared with fecal fat excretion. Patients and Methods: 21 patients with CF-PS performed the 3 tests of fecal fat excretion, fecal elastase-1, and IRT. Correlation between the tests was evaluated by the k statistics test, sensitivity and specificity, and positive and negative predictive values. Results: CFA was abnormal in 5 patients, elastase was <200 mg/g in 4 patients, and IRT was <20 ng/mL in 2 patients. The correlation between CFA and IRT was negative (k ¼ À0.154), and between CFA and fecal elastase-1 was poor (k ¼ 0.213). The sensitivity, specificity, and positive and negative predictive values of IRT versus CFA were 0%, 88%, 0%, and 78%, and for fecal elastase-1 were 40%, 81%, 40%, and 81%, respectively. Conclusions: In CF-PS, poor correlation was found between IRT, fecal elastase-1, and CFA, therefore neither fecal elastase-1 in the stool nor IRT in the serum reaches the sensitivity or the specificity of the fecal fat excretion. Thus, fecal fat excretion is required in patients with CF for evaluation of pancreatic function. JPGN 48:306-310, 2009.
Objective: To describe prostanoid DP receptor (PTGDR) variants in women with preterm births who a... more Objective: To describe prostanoid DP receptor (PTGDR) variants in women with preterm births who admitted to coital activity (CA) within 24 h of labor. Study Design: To achieve >80% statistical power, a pilot case-control study compared 24 premature births from mothers with CA (Group 1), 30 mothers of premature infants who did not have CA (Group 2 non-coital activity) and 95 non-coital activity mothers with term births (Group 3 controls). Four functional PTDGR single nucleotide polymorphisms (SNPs) were evaluated: T-549C, C-441/T, T-197C and G þ 1044A. PHASE 2.0.2 and SAS 9.2 were used for analysis. Result: All SNPs were in Hardy-Weinberg equilibrium in controls. The C-441/T genotype frequency was significantly increased among Group 1 women relative to Group 2 and 3 women (odds ratio (OR): 30.1, 95% confidence interval (CI) 6.9-191 and 25.7 95%CI 25.7-not computible, respectively). Of the possible haplotypes among the groups, the TCTG haplotype (T-549C, C-441/T, T-197C and G þ 1044A) was significantly more frequent in Group 1 women compared with the control groups (OR 53.4, 95%CI 10.3-554.8). Conclusions: A differential genomic pattern of PTGDR polymorphisms was identified in a subset of mothers which was associated with an increased risk of post-coital preterm birth.
What are the success rates of social oocyte cryopreservation (SOC) at advanced age? In this study... more What are the success rates of social oocyte cryopreservation (SOC) at advanced age? In this study, one in four women who underwent SOC above age 35 had a delivery. While SOC is gaining popularity, reports on delivery rates are limited due to low utilization rates. Retrospective data collection of all woman who underwent SOC between 2011–2018, and presented for treatment using cryopreserved oocytes until January 2021. Participants/materials, setting, methods: Review of patient records (including both IVF and antenatal/postnatal) and laboratory data in a university affiliated hospital-based IVF unit. Main results and the role of chance: A total of 448 women underwent SOC during 2011–2018. 50 (11.2%) women returned to use these oocytes until the end of January 2021. Women who returned to use their oocytes underwent cryopreservation at mean age of 38.2±2.2. 46 (92%) of participants were above 35 at time of cryopreservation. Number of oocytes cryopreserved was 11.3±9.7. Mean time from cr...
Journal of Osteoporosis and Physical Activity, 2017
Introduction: Prader-Willi syndrome (PWS (is caused by lack of paternally expressed imprinted gen... more Introduction: Prader-Willi syndrome (PWS (is caused by lack of paternally expressed imprinted genes at chromosome 15q11.2-q13. Diminished (BMD) and osteoporosis are common in PWS. The purpose of this study was to determine whether polymorphisms in genes previously shown to correlate with bone mineral density (BMD), might explain the variable expression of abnormal BMD in PWS. Material and methods: Blood samples were collected from 96 PWS individuals aged 3.5-47.9 (median 14.4) years. DNA samples were tested for 12 polymorphisms in 8 candidate genes: interleukin-1 (IL1-alfa, IL1-beta and IL1RN), CYP1A1, Low Density Lipoprotein Receptor-Related Protein 5 (LRP5), vitamin D receptor (VDR), RANK and RANKL. All patients underwent BMD measurements at the femoral neck and lumbar spine using a hologic dual energy x-ray absorptiometry (DXA) machine. Results: Abnormal BMD was defined as Z-score <-1.5. Severe reduced BMD as Z-score <-2.5. 67 subjects (70%) had abnormal BMD (youngest 3.7 y...
Gynecologic and obstetric investigation, Jan 13, 2017
The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramus... more The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramuscular (IM) progesterone. This is a randomized clinical trial. Patients assigned to a medicated day 5 frozen embryo transfer (FET) were randomly allocated to "vaginal progesterone" or "IM progesterone": patients randomized to the vaginal arm were treated with 200 mg micronized progesterone 3 times daily while patients randomized into the IM progesterone arm were treated with a single daily injection of 50 mg progesterone in oil. The main outcome measure was the number of sub-endometrial contractions (waves) per minute 1 day before a blastocyst embryo transfer. Thirty-four patients were enrolled. The progesterone serum concentration was significantly higher in patients using the IM progesterone (85.2 ± 50.1 vs. 30.3 ± 11.2 nmol/L, respectively) but this did not translate into a lower sub-endometrial contractility (2.4 ± 4.8 vs. 1.4 ± 1.1 contraction/min, respectively). ...
Research Question We sought to determine why women facing poor prognoses for success in Assisted ... more Research Question We sought to determine why women facing poor prognoses for success in Assisted Reproductive Technologies (ART) choose to pursue treatments using their own eggs, despite receiving information that their chances for success are very low. Design A cross-sectional study based on an anonymous questionnaire distributed to female patients aged 43-45, undergoing ART using their own oocytes, at six public outpatient fertility clinics and three public in-hospital IVF units in Israel during the years 2015-2016. The main outcome measure was personal estimation of chance to achieve a live birth following the current ART treatment cycle and the cumulative estimated rate following all the treatment cycles the patient intended to undergo. Results Response rate was 70.0%. Mean age of participants was 43.8±0.7 years. Participants estimated their delivery rates following the next ART treatment cycle at 49.0 ± 31.8 % and their cumulative delivery rates after all the ART treatments they would undergo at 57.7 ± 36.2%. This is significantly higher than the predicted success rates of 5% and 15%, respectively, that are based on national register data. Nearly half rated themselves as having a better than the average chance of conception (47.3%). Conclusion Women do not pursue futile treatments because they lack information. Despite being informed of the low success rates of conception using ART treatments, many advanced maternal age patients have unrealistically high expectations from ART, essentially ignoring their estimated prognosis when deciding on treatment continuation. Future work should examine the psychological reasons behind continuing futile fertility treatments.
Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant an... more Mammalian oocyte quality reduces with age. We show that prior to the occurrence of significant aneuploidy (9M in mouse), heterochromatin histone marks are lost, and oocyte maturation is impaired. This loss occurs in both constitutive and facultative heterochromatin marks but not in euchromatic active marks. We show that heterochromatin loss with age also occurs in human prophase I‐arrested oocytes. Moreover, heterochromatin loss is accompanied in mouse oocytes by an increase in RNA processing and associated with an elevation in L1 and IAP retrotransposon expression and in DNA damage and DNA repair proteins nuclear localization. Artificial inhibition of the heterochromatin machinery in young oocytes causes an elevation in retrotransposon expression and oocyte maturation defects. Inhibiting retrotransposon reverse‐transcriptase through azidothymidine (AZT) treatment in older oocytes partially rescues their maturation defects and activity of the DNA repair machinery. Moreover, activating the heterochromatin machinery via treatment with the SIRT1 activating molecule SRT‐1720, or overexpression of Sirt1 or Ezh2 via plasmid electroporation into older oocytes causes an upregulation in constitutive heterochromatin, downregulation of retrotransposon expression, and elevated maturation rates. Collectively, our work demonstrates a significant process in oocyte aging, characterized by the loss of heterochromatin‐associated chromatin marks and activation of specific retrotransposons, which cause DNA damage and impair oocyte maturation.
Mammalian oocyte quality reduces with female age. A well-studied aspect of this deterioration is ... more Mammalian oocyte quality reduces with female age. A well-studied aspect of this deterioration is an age-associated rise in oocyte aneuploidy. We show that prior to the occurrence of significant aneuploidy (at the age of 9 months in mouse females), epigenetic changes occur and impact oocyte quality and maturation ability. At this age- we observe a reduction in heterochromatin marks in mouse oocytes. This decrease is apparent in both constitutive heterochromatin and facultative heterochromatin marks but is absent in active euchromatic marks which remain constant. A decrease of heterochromatin marks with age is also observed in human GV oocytes from IVF treatments. Heterochromatin loss with age is associated with an elevation in retrotransposon RNA transcription and processing, an elevation in retrotransposon protein expression, elevation in DNA repair proteins nuclear localization and oocyte maturation defects. Artificial inhibition of the heterochromatin machinery in young oocytes ca...
Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regress... more Anti-Mullerian hormone (AMH), secreted by immature testicular Sertoli-cells, triggers the regression of male fetal Mullerian ducts. During puberty, AMH is downregulated by intratesticular testosterone. In females, AMH is secreted from granulosa cells of immature ovarian follicles from late prenatal life until menopause; serum concentration is 5-20 times lower in females than in males through lifetime. In boys, AMH determination is useful in the clinical setting as a marker of Sertoli cell function. Serum AMH is low in infants with hypogonadotrophic hypogonadism (and increases with FSH treatment), in patients with primary hypogonadism from early postnatal life and in Klinefelter syndrome from midpuberty. In boys with nonpalpable gonads, AMH determination is useful to distinguish between cryptorchidism and anorchism, as well as differentiating the dysgenetic causes of disorders of sexual development from those due to defective androgen synthesis or action. AMH can be used as a marker ...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2014
To determine whether the decrease in AMH levels during ovarian hyperstimulation for IVF occurs in... more To determine whether the decrease in AMH levels during ovarian hyperstimulation for IVF occurs in patients with polycystic ovary syndrome (PCOS) and patients with low ovarian reserve (LOR), as in normal cycling women.
Research Question We sought to determine why women facing poor prognoses for success in Assisted ... more Research Question We sought to determine why women facing poor prognoses for success in Assisted Reproductive Technologies (ART) choose to pursue treatments using their own eggs, despite receiving information that their chances for success are very low. Design A cross-sectional study based on an anonymous questionnaire distributed to female patients aged 43-45, undergoing ART using their own oocytes, at six public outpatient fertility clinics and three public in-hospital IVF units in Israel during the years 2015-2016. The main outcome measure was personal estimation of chance to achieve a live birth following the current ART treatment cycle and the cumulative estimated rate following all the treatment cycles the patient intended to undergo. Results Response rate was 70.0%. Mean age of participants was 43.8±0.7 years. Participants estimated their delivery rates following the next ART treatment cycle at 49.0 ± 31.8 % and their cumulative delivery rates after all the ART treatments they would undergo at 57.7 ± 36.2%. This is significantly higher than the predicted success rates of 5% and 15%, respectively, that are based on national register data. Nearly half rated themselves as having a better than the average chance of conception (47.3%). Conclusion Women do not pursue futile treatments because they lack information. Despite being informed of the low success rates of conception using ART treatments, many advanced maternal age patients have unrealistically high expectations from ART, essentially ignoring their estimated prognosis when deciding on treatment continuation. Future work should examine the psychological reasons behind continuing futile fertility treatments.
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Papers by Amir Weintraub