Leiomyomas, monoclonal tumors developed by the transformation of myometrium somatic stem cells, are a major health concern that can severely impair quality of life. Pathological alterations of signaling pathways have been recognized as a key feature in a variety of human diseases. Our objective was to analyze treatment with all‐trans‐retinoic acid (ATRA) by suppression of the phosphoinositide 3‐kinase (PI3K) pathway on growth, signaling pattern and interactions among PI3K/B‐cell lymphoma 2 (Bcl2)/retinol leiomyoma proteins.

Objective: To compare the physical and emotional effects of two medical protocols for induced abortion during the second trimester. Methods: The present study was part of a prospective randomized controlled trial comparing mifepristone followed by oxytocin or misoprostol that was conducted at the Hadassah Hebrew University Medical Center, Jerusalem, Israel, from January 10, 2009, to February 22, 2012. Inclusion criteria were pregnancy (14-24 weeks), epidural analgesia, and medical induction of abortion (either elective or following missed abortion). A structured questionnaire was used to assess the participants' physical symptoms and emotional responses. The primary outcome for the present analysis was the degree of physical symptoms reported. Results: Overall, 68 women in the oxytocin group and 67 in the misoprostol group received epidural analgesia and completed the questionnaire. As assessed using a five-point Likert scale, women in the misoprostol group were more likely than those in the oxytocin group to experience diarrhea (1.34 +/- 0.84 vs 1.10 +/- 0.55; P = 0.05) and shivers (3.03 +/- 1.75 vs 1.75 +/- 1.21; P < 0.001). No other between-group differences were detected for the physical or emotional variables evaluated. Conclusion: Differences in physical symptoms experienced by the two treatment groups did not influence the participants' subsequent emotional response. ClinicalTrials.gov: NCF00784797 (C) 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE: To compare two methods for induction of second-trimester abortion after priming the cervix with mifepristone.METHODS: This was a randomized prospective trial carried out between January 2009 and February 2012. The participants were healthy women between 14 and 24 weeks of gestation with missed miscarriage or need for termination of pregnancy. All participants received oral 200 mg mifepristone and, after 36 hours, after randomization, were given either a high-concentration oxytocin drip (maximal dose of 150 milli-international units/min) for up to 36 hours or 800 micrograms misoprostol vaginally followed by 400 micrograms oral misoprostol every 3 hours with a maximum of four oral doses. If expulsion of the fetus was not achieved, another 200 mg mifepristone was administered and another course of misoprostol was delivered as described previously. The primary outcome measure was success expulsion of the fetus in 36 hours since starting on uterotonic agent. Secondary outcomes included time until expulsion of the fetus and rate of adverse outcomes.RESULTS: Success rates in the mifepristone-misoprostol and mifepristone-oxytocin arms were 100% (70/70 patients) and 95.8% (69/72), respectively (relative risk 1.043, 95% confidence interval 0.99-1.10, P=.13). Time until fetal expulsion was shorter in the mifepristone-misoprostol arm (7.0 +/- 4.9 hours compared with 11.3 +/- 7.4 hours, P<.001). However, the rate of adverse effects in the misoprostol group was higher than in the oxytocin group. Factors associated with a shorter time until expulsion were missed miscarriage compared with therapeutic abortion, increased ultrasonographic gestational age, and increased parity.CONCLUSION: The two regimens studied had comparable efficacy for induction of second-trimester abortion; however, the mifepristone-oxytocin regimen has a longer time until expulsion but with fewer side effects.

OBJECTIVE:To detect changes induced by all-trans-retinoic acid (ATRA) on the expression and activation of target proteins of the retinoic acid (RA) and PI3K/Akt pathways involved in leiomyoma growth. DESIGN:A study on human tissue cultures. SETTING:Hadassah University Hospital. PATIENT(S):Premenopausal women with uterine leiomyomas. INTERVENTION(S):Paired cultures of normal myometrium and leiomyomas, from women undergoing hysterectomy, were obtained. MAIN OUTCOME MEASURE(S):The effect of ATRA was examined on the expression and phosphorylation of relevant RA, PI3K/Akt, and Bcl2 proteins (immunochemical analysis), cell proliferation, cell cycle distribution, and apoptosis. RESULT(S):Applying our cell culture model, we demonstrated that ATRA induced changes in the expression and activation of the RA and PI3K/Akt pathway proteins in leiomyoma cells, with significant increases of alcohol dehydrogenase 1 and cyclin D2 protein levels. In part of the leiomyoma cells, ATRA induced a relative increase of Bax (proapoptotic) as well as a relative decrease of phosphorylated glycogen synthase kinase 3β (proapoptotic). CONCLUSION(S):Our results highlight the involvement of ATRA in the RA and PI3K/Akt pathways, whose specific signaling products may influence the outcome of leiomyoma growth by regulating cell proliferation, apoptosis, and survival. These results might be useful for the on-going research into alternative methods for treating and preventing this disorder.

Background. Secondary post-partum hemorrhage (PPH) is defined as any abnormal bleeding from the birth canal occurring between 24 hours and 12 weeks postnatally. Treatment usually falls into one of the two categories: surgical evacuation of the uterus or medical treatment. Objective. To compare the two different clinical approaches and the implications on future fertility. Study design. A retrospective study. Setting . From 1990 to 2002, 168 women diagnosed with late PPH were admitted to the Hadassah Medical Centers in Jerusalem. The cases were divided into two groups according to the planned initial treatment: primary surgical treatment vs. primary medical treatment. Results . Primary surgical treatment was associated with significantly more primary negative events ( p = 0.01). After the primary event, primary surgical treatment was associated with fewer future deliveries ( p = 0.04) and resulted in increased rate of secondary infertility of borderline significance ( p = 0.06). Conclusions. Our results show that secondary PPH is related to high rates of immediate and long-term complications. It is possible that a conservative medical approach for secondary PPH may be superior to surgical treatment.

Allen-Masters syndrome, first described at 1955, is considered an uncommon etiology for chronic pelvic pain. The syndrome associates traumatic delivery to lacerations found on the posterior leaf of the broad Ligament. The authors report the clinical and laparoscopic findings of a female patient who was admitted to their department for evaluation due to chronic pelvic pain. The patient had a history of normal delivery six months before her admission. In the laparoscopy the authors reported finding bilateral Lacerations in the posterior leaf of the broad Ligament. Coagulation of both lacerations was performed and the patient reported significant improvement in her complaints. The relevant literature was reviewed and the article discusses the process of diagnosis and treatment.

Isolated fallopian tube torsion (ITT) is a rare condition defined as a total or partial rotation of the fallopian tube around its vascular axis. The torsion initiaLLy interferes with the venous and lymphatic circulation. If unrelieved in time, rapid progression occurs, occluding the arterial circulation and Leading to gangrene and hemorrhagic necrosis. The cLinicaL appearance usually includes sharp lower abdominal pain, with or without peritoneal signs. Urinary and gastrointestinal signs might also occur. isolated fallopian tube is a rare condition; the incidence s estimated to be 1:500,000 mostly in reproductive age women. ITT is most common in the right side, although several reports claim that there is no difference between the sides. The etiology is not completely understood, but tubal anomalies (anatomic or physiologic) as well as trauma or pelvic inflammation are predisposing factors. The clinical appearance and the imaging in these cases are not pathognomonic, and many cases are delayed by means of diagnosis and treatment. The treatment is surgical. Detorsion or salpingectomy is usually performed by laparoscopy. Three cases that were treated lately at the Department of Obstetrics and Gynecology at the Hadassah Medical Center are presented together with a review of the literature.

Objective: To identify changes in the expression and phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt protein kinases controlling survival and/or apoptosis of in vitro cell cultures of uterine leiomyomas.Design: Establishment of paired cell cultures of leiomyoma and myometrial specimens.Setting: Hadassah gynecology research laboratory.Patient(s): Eleven white premenopausal women, 35 to 50 years of age, undergoing hysterectomy because of symptomatic uterine leiomyomas.Intervention(s): None.Main Outcome Measure(s): Immunochemical analysis of expression and phosphorylation of relevant PI3K/Akt and BCL2 proteins.Result(s): Analysis of total phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and of non-phosphorylated and phosphorylated (p) PDK1, Akt, glycogen synthase kinase 3 (GSK3), FKHR, tuberin (TSC2) and hamartin (TSC1) complex, and cyclin D2 proteins indicated that [1] the level of pGSK3 alpha and cyclin D2 proteins was elevated significantly in the leiomyoma compared with the normal myometrium, [2] there was a significant interaction between PTEN-PDK1 and between pAkt-pGSK3 beta in the leiomyoma compared with the myometrial cells, and [3] there was a significant interaction between pAkt-pGSK3 alpha in the paired leiomyoma and myometrial cultures.Conclusion(s): Our study suggests that the downstream signaling components of the PI3K/Akt pathway, GSK3 (a regulator of apoptosis), and cyclin D2 (a promoter of G1/S progression), as well as the significant interaction between PTEN-PDK and between pAkt-pGSK3 beta, are involved in the survival and proliferation of leiomyomas. (Fertil Steril (R) 2010; 93: 2646-51. (C) 2010 by American Society for Reproductive Medicine.)

Objective: To examine the effect of alcohol and its derivatives on leiomyomata versus normal myometrium in cell culture.Design: A study on human tissue cultures.Setting: A tertiary-care university hospital.Patient(s): Premenopausal women with uterine myomas.Intervention(s): Obtaining paired cultures of normal myometrium and myomas from women undergoing hysterectomy.Main Outcome Measure(s): Analysis of the effect of ethanol and acetaldehyde on cell growth and the expression of relevant proteins.Result(S): Acetaldehyde statistically significantly inhibited the growth of myoma cells compared with normal myometrium. The level of alcohol dehydrogenase 1 (ADH1) protein was lower in myoma than in myometrial cells. The acetaldehyde dehydrogenase 1 (ALDH 1) protein level was higher in myoma cells. Treatment with acetaldehyde resulted in a relative reduction of ALDH1 level in the myoma cells.Conclusion(S): Acetaldehyde has an inhibitory effect on cell growth of myoma compared with normal myometrium. The reduced level of ADHI and the increased level of ALDH1 proteins observed in myoma cell culture reduces the acetaldehyde level and thus may be involved in myoma cell growth. (Fertil Steril(R) 2009;91:575-9. (C)2009 by American Society for Reproductive Medicine.)

BACKGROUND AND AIMS:microRNAs (miRNAs) are small noncoding RNAs that regulate cognate mRNAs post-transcriptionally. miRNAs have been implicated in regulating gene expression in embryonic developmental processes, including proliferation and differentiation. The liver is a multifunctional organ, which undergoes rapid changes during the developmental period and relies on tightly-regulated gene expression. Little is known regarding the complex expression patterns of both mRNAs and miRNAs during the early stages of human liver development, and the role of miRNAs in the regulation of this process has not been studied. The aim of this work was to study the impact of miRNAs on gene expression during early human liver development.METHODS:Global gene and miRNA expression were profiled in adult and in 9-12w human embryonic livers, using high-density microarrays and quantitative RT-PCR.RESULTS:Embryonic liver samples exhibited a gene expression profile that differentiated upon progression in the developmental process, and revealed multiple regulated genes. miRNA expression profiling revealed four major expression patterns that correlated with the known function of regulated miRNAs. Comparison of the expression of the most regulated miRNAs to that of their putative targets using a novel algorithm revealed a significant anti-correlation for several miRNAs, and identified the most active miRNAs in embryonic and in adult liver. Furthermore, our algorithm facilitated the identification of TGFbeta-R1 as a novel target gene of let-7.CONCLUSIONS:Our results uncover multiple regulated miRNAs and genes throughout human liver development, and our algorithm assists in identification of novel miRNA targets with potential roles in liver development.

Background. Secondary post‐partum hemorrhage (PPH) is defined as any abnormal bleeding from the birth canal occurring between 24 hours and 12 weeks postnatally. Treatment usually falls into one of the two categories: surgical evacuation of the uterus or medical treatment. Objective. To compare the two different clinical approaches and the implications on future fertility. Study design. A retrospective study. Setting . From 1990 to 2002, 168 women diagnosed with late PPH were admitted to the Hadassah Medical Centers in Jerusalem. The cases were divided into two groups according to the planned initial treatment: primary surgical treatment vs. primary medical treatment. Results . Primary surgical treatment was associated with significantly more primary negative events ( p = 0.01). After the primary event, primary surgical treatment was associated with fewer future deliveries ( p = 0.04) and resulted in increased rate of secondary infertility of borderline significance ( p = 0.06). Conclusions. Our results show that secondary PPH is related to high rates of immediate and long‐term complications. It is possible that a conservative medical approach for secondary PPH may be superior to surgical treatment.

Background The most effective strategy for prevention of ovarian and breast cancer in high-risk women is bilateral salpingo-oophorectomy. The inevitable consequence of the procedure is early menopause with the associated climacteric symptoms. Little is known about the nature of the symptoms in women who undergo risk-reducing bilateral salpingo-oophorectomy.Objectives To compare the nature, frequency, severity, duration, and overall effects of climacteric symptoms in a group of women who underwent preventive bilateral salpingo-oophorectomy as compared to women who experienced natural menopause.Methods Forty-eight women at high risk for ovarian cancer who had risk-reducing bilateral salpingo-oophorectomy were compared to 60 postmenopausal women who had natural menopause. The participants were interviewed about their climacteric complaints, thoughts and feelings regarding the surgical procedure and their general well-being. The climacteric symptoms were evaluated by a modified Greene Climacteric Scale.Results Surgical menopause, as compared to natural menopause, was associated with more severe psychological, vasomotor and somatic climacteric symptoms (total score 17.36 vs. 8.65, respectively, p < 0.001) and more significant sexual dysfunction (1.848 vs. 0.900, respectively, p < 0.01). On a 0–10 scale, the satisfaction rate from the surgical procedure was 8.23 ± 2.21. The surgery did not affect the perceived quality of life (p = 0.347) and decreased the score of anxiety and cancer fear (from 7.75 ± 3.31 preoperatively to 2.94 ± 3.08 postoperatively, p < 0.001).Conclusions Risk-reducing bilateral salpingo-oophorectomy as compared to natural menopause is associated with more severe climacteric symptoms. However, the procedure does not interfere with the overall perceived quality of life and improves the perception of cancer risk.

Despite the tremendous impact of uterine fibroids on womens’ quality of life and health economy, the mechanism of their development remains an enigma. Several mechanisms have been suggested, including endocrine, paracrine and genetic theories. A number of lines of evidence support a genetic basis for uterine fibroid formation. These include ethnic variation, familial predisposition, twin studies and unique familial syndromes. In 1973 Reed et al. described a syndrome of familial cutaneous and uterine leiomyomata [ [1] Reed W.B. Walker R. Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol. 1973; 53: 409-416 PubMed Google Scholar ]. Tomlinson et al. have demonstrated that germ-line mutations in the gene for fumarate hydratase (fumarase), a Krebs-cycle enzyme, predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell carcinoma [ [2] Tomlinson I.P. Alam N.A. Rowan A.J. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002; 30: 406-410 Crossref PubMed Scopus (1212) Google Scholar ]. Recently, it has been shown that fumarate hydratase mutations are involved also in non-syndromatic uterine leiomyomas [ [3] Gross K.L. Panhuysen C.I.M. Kleinman M.S. et al. Involvement of fumarate hydratase in non-syndromatic uterine leiomyomata: genetic linkage analysis and FISH studies. Genes Chromosomes Cancer. 2004; 41: 183-190 Crossref PubMed Scopus (59) Google Scholar ]. Given these genetic data, we set out to measure the level of this enzyme, at the protein level, in leiomyoma and in normal myometrial tissues and to correlate its levels with family history. We hypothesized that family history is inversely related to fumarate hydratase levels in the myoma cells. After obtaining IRB approval and informed consent as required, paired cell cultures of leiomyoma and adjacent normal myometrium tissue samples were obtained from hysterectomy specimens of 14 pre-menopausal women with a symptomatic fibroid uterus. Our techniques for myoma/myometrium cell cultures have been described in detail elsewhere [ [4] Shveiky D. Shushan A. Ben Bassat H. et al. Acetaldehyde differentially affects the growth of uterine leiomyomata and myometrial cells in tissue cultures. Fertil Steril. 2009; 91: 575-579 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar ]. Fumarate hydratase levels in leiomyoma and myometrium were analyzed by Western blot and compared with family history of symptomatic fibroids. Clinical data were obtained from patient's charts and telephone interviews. Significant family history of fibroids was defined as at least one first-degree relative with symptomatic uterine fibroids requiring surgery. Descriptive and univariate analyses were used to determine statistical significance (p < 0.05). Our results showed that patients who had positive family history of symptomatic fibroids had significantly lower levels of fumarate hydratase in the leiomyoma cells compared to the myometrium (p = 0.011, Fig. 1). There were no differences in patients’ demographics, clinical presentation and uterine size between the groups.

OBJECTIVETo study the effect of mifepristone for priming and induction of second-trimester abortion in conjunction with a high-concentration oxytocin drip.STUDY DESIGNProspective, randomized, placebo-controlled, pilot study. Thirty patients with 14-25 weeks' gestational age abortion received either 600 mg of mifepristone or placebo in 3 identical capsules followed, 48 hours later, by a high-concentration oxytocin drip (HCOD).RESULTSThe mifepristone group showed significantly higher success rates as compared to the placebo group (92.3% vs. 52.9%, p<0.05). The time interval to abortion (from beginning of HCOD) was also significantly shorter in the mifepristone group as compared to the placebo group (11.3 +/- 6.0 hours vs. 17.6 +/- 6.5 hours, p <0.05). Probability of success as calculated by the Kaplan-Meier method was found to be highly significant (log rank test p = 0.001).CONCLUSIONOur results suggest that mifepristone is very effective for priming and induction of second-trimester abortion and shortens significantly the time interval to evacuation following HCOD.

Background: Ehlers-Danlos syndrome is a heterogeneous group of connective tissue disorders, characterized by a defect in the synthesis of collagen. The syndrome is subdivided into different clinical subtypes, the most hazardous of which is type IV, the vascular type. It can manifest itself in various complications such as rupture of arteries and hollow organs. The obstetrical manifestations are the risk of uterine rupture during labor, damage to the vagina and perineum, bleeding and rupture of blood vessels and colon during the puerperium. Case Report: We describe a primigravida suffering from Ehlers-Danlos type IV who was followed and successfully delivered by a cesarean section at 36 weeks of gestation and made an uneventful recovery. Conclusion: Following a thorough literature review, it seems wise to perform early delivery by cesarean section for pregnant women suffering from Ehlers-Danlos type IV.

OBJECTIVE: To study whether osteopenia occurs following pregnancy and to evaluate its severity in young primiparas.STUDY DESIGN: A prospective case control study. Sixty-one young primigravidae early after birth and 59 nulligravidae matched for age and BMI participated in the study. Bone status was examined using ultrasonic bone transmission velocity over the tibia; Z-score and T-score for bone density were calculated. Serum bone alkaline phosphatase, osteocalcin and urinary N-telopeptide crosslinks were evaluated as bone remodeling biochemical markers.RESULTS: Ultrasonic parameters of bone status following delivery were significantly lower in the puerperal group as compared to the nulligravida group. Serum mean bone alkaline phosphatase levels and urinary N-telopeptide crosslinks secretion were higher by 50% in the puerperal group, while serum osteocalcin levels were significantly lower (by 25%) than in the nulligravida controls. A positive correlation between ultrasonic measurements and biochemical markers was demonstrated in the postpartum group, whereas the control group showed a negative correlation.CONCLUSION: Women at their early puerperium demonstrate a significant cortical bone mass reduction as measured by ultrasonograph and markers of bone turnover. It appears that pregnancy is a state Of unbalanced accelerated bone turnover that may be associated with reduced osteoblastic activity.

BACKGROUND:Ehlers-Danlos syndrome is a heterogeneous group of connective tissue disorders, characterized by a defect in the synthesis of collagen. The syndrome is subdivided into different clinical subtypes, the most hazardous of which is type IV, the vascular type. It can manifest itself in various complications such as rupture of arteries and hollow organs. The obstetrical manifestations are the risk of uterine rupture during labor, damage to the vagina and perineum, bleeding and rupture of blood vessels and colon during the puerperium.CASE REPORT:We describe a primigravida suffering from Ehlers-Danlos type IV who was followed and successfully delivered by a cesarean section at 36 weeks of gestation and made an uneventful recovery.CONCLUSION:Following a thorough literature review, it seems wise to perform early delivery by cesarean section for pregnant women suffering from Ehlers-Danlos type IV.

"Fallopian tube carcinoma presenting as an endometrial polyp." Journal of Obstetrics and Gynaecology, 27(2), pp. 215–216

Two cases of septic complications of routine second trimester amniocentesis are presented. The first case is a 37-year-old gravida suffering from ulcerative colitis who was admitted for amniocentesis in the 18th week of her third pregnancy. An uncomplicated transabdominal amniocentesis was performed using a sterile technique and ultrasound guidance. Twenty-eight hours later the patient had a septic abortion and sepsis. The second case is a 34-year-old gravida in the 24th week of her pregnancy who was admitted with amnionitis 10 h after an uncomplicated amniocentesis, and subsequently had a septic abortion. A high index of suspicion and rapid intervention were crucial in both cases.

Objective: To determine the potency of TKS050, a new epidermal growth factor receptor (EGFR) inhibitor and genistein, a naturally occurring protein tyrosine kinase inhibitor, to inhibit leiomyoma cell proliferation in vitro.Design: Establishment of paired cultures of leiomyoma and normal myometrial samples.Setting: University clinical research laboratory.Patient(s): Hysterectomy specimens from premenopausal women affected by uterine leiomyomas.Intervention(s): The suppressive effect of TKS050 and genistein on the cells, before and after steroidal hormone treatment, was examined.Main Outcome Measure(s): Cell proliferation, recovery after treatment, cell cycle analysis. and immunochemical analysis of relevant proteins were performed.Result(s): TKS050 (2 mu mol/L) and genistein (50 mu mol/L) completely suppressed leiomyoma cell proliferation, and the cells did not recover after cessation of treatment. TKS050 induced cell cycle arrest and apoptosis in a dose- and time-dependent manner. Cells accumulated in the G(0)/G(1) phase of the cell cycle at the expense of the S and G(2)+M phases. Treatment of cells with TKS050 resulted in a dose-dependent inhibition of EGFR autophosphorylation and of phosphorylated signal transducer and activator of transcription 3 (Stat3). Genistein inhibited the phosphorylated Stat3 but did not affect EGFR autophosphoryation. The inhibitory effects of TKS050 or genistein were unaffected by the presence of physiologic concentrations of estradiol-17 beta.Conclusion(S): Leiomyoma cell growth is effectively blocked by TKS050 and genistein. The inhibitory action of newly developed and natural inhibitors derived from diet may be useful as a,possible alternative therapy for leiomyomas.