Yuval Bdolah

Soluble endoglin contributes to the pathogenesis of preeclampsia.

Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-β coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-β1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-β signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.

Endometrial NK Cells Are Special Immature Cells That Await Pregnancy

NK cells populate the human endometrium before pregnancy. Unlike decidual NK cells that populate the decidua during pregnancy, the NK cells present in the human endometrium, before pregnancy, have not been fully characterized. In this study, we provide a detailed analysis of the origin, phenotype, and function of endometrial NK cells (eNK). We show that eNK cells have a unique receptor repertoire. In particular, they are negative for NKp30 and chemokine receptor expression, which distinguishes them from any other NK subset described so far. We further show that eNK cells lack NK-specific functional phenotype and activity such as cytokine secretion and cytotoxicity, before IL-15 stimulation. Following such stimulation, endometrial NK cells acquire phenotype and function that are similar to those of decidual NK cells. We therefore suggest that eNK cells are inactive cells (before IL-15 activation and in relation to the known NK activity) that are present in the endometrium before conception, waiting for pregnancy.

Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?

OBJECTIVE Twin pregnancies are a risk factor for preeclampsia with a reported incidence of 2-3 times higher than singleton pregnancies. Soluble fms-like tyrosine kinase 1 (sFlt1), which is a circulating antiangiogenic molecule of placental origin, plays a central role in preeclampsia by antagonizing placental growth factor (PlGF) and vascular endothelial growth factor signaling in the maternal vasculature. Increased sFlt1 and the ratio sFlt1/free PlGF have been shown to antedate clinical signs in preeclampsia. Although the cause of the upregulated sFlt1 in preeclampsia still is not understood clearly, placental ischemia with accompanying hypoxia is thought to play an important role. We therefore hypothesized that the higher risk of preeclampsia in twin pregnancies results from high sFlt1 (or sFlt1/PlGF) and that the sFlt1 upregulation was due to either relative placental hypoxia and/or increased placental mass. STUDY DESIGN Maternal serum samples and placentas from third-trimester twin and singleton pregnancies without preeclampsia were used. Serum samples were analyzed for levels of sFlt1 and free PlGF by enzyme-linked immunosorbent assay and reported as means (in nanograms per milliliter and picograms per milliliter, respectively). Placentas were weighed and examined for content of sFlt1 and PlGF messenger RNA (mRNA) by quantitative polymerase chain reaction and hypoxia inducible factor-1alpha (HIF-1alpha) protein by Western blot. RESULTS Soluble Flt1 concentrations in twin pregnancy maternal serum were 2.2 times higher than those that were measured in singleton pregnancy maternal serum samples (30.98 +/- 9.78 ng/mL vs 14.14 +/- 9.35 ng/mL, respectively; P = .001). Free PlGF concentrations were not significantly different between twin and singleton maternal serum samples, but the mean sFlt1/PlGF ratio of twin pregnancy maternal serum samples was 2.2 times higher than the equivalent ratio in singleton pregnancy samples (197.58 +/- 126.86 ng/mL vs 89.91 +/- 70.63 ng/mL, respectively; P = .029). Quantitative polymerase chain reaction for sFlt1 and PlGF mRNA revealed no significant differences between the 2 study groups. Western blot analysis of placental samples for HIF-1alpha revealed a mean ratio HIF-1alpha/actin of 0.53 vs 0.87, for the twins vs singletons placental samples respectively (twins showed lower HIF-1alpha, not higher). The mean weights of twin and singleton placentas were 1246 vs 716 g, respectively (P < .001). Importantly, the placental weights correlated very well with the circulating sFlt1 levels (R(2) = .75). CONCLUSION In twin pregnancies, circulating sFlt1 levels and sFlt1/PlGF ratios were twice as high as those in singleton pregnancies. The increased serum sFlt1 levels in twin pregnancies were not accompanied by any changes in the levels of sFlt1 mRNA and HIF-1alpha protein in the twin placentas but were correlated with increased placental weight. These findings suggest that the increased risk of preeclampsia in twin pregnancies may be due to increased placental mass that leads to increased circulating levels of sFlt1.

Reproductive outcome of fresh or frozen–thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support

BACKGROUND Triggering ovulation by GnRH agonist (GnRHa) in GnRH antagonist IVF protocols coupled with adequate luteal phase support has recently been suggested as a means to prevent ovarian hyperstimulation syndrome (OHSS). Our objective was to examine the outcome of fresh embryo transfer (f-ET) after triggering ovulation by GnRHa and providing intensive luteal phase supplementation, compared with that of the next first frozen-thawed embryo transfer (ft-ET) after cycles with the same protocol and cryopreservation of all the embryos. METHODS We performed a cohort study at a university-based IVF clinic. The study population was patients at high risk for OHSS. A daily dose of 50 mg i.m. progesterone in oil and 6 mg of oral 17-β-estradiol initiated on oocyte retrieval day in the f-ET group (n= 70). In the ft-ET group (n= 40) the embryos were cryopreserved and transferred in the next cycle. RESULTS The live birth rate per f-ET was 27.1 versus 20% in the ft-ET groups [P = 0.4; rate ratio = 1.36 (0.65-2.81)]. The implantation, pregnancy and spontaneous abortion rates were comparable in both groups. None of the patients developed OHSS. CONCLUSIONS In this observational cohort study, we showed that triggering ovulation with GnRHa and intensive luteal phase support is a promising new modality to prevent OHSS without the cost of cycle cancellation, ET deferral and reduced clinical pregnancy rates. Confirmation of these findings by RCTs is now required.

The value of repeat testicular sperm retrieval in azoospermic men

To determine the predictive value of a previous testicular biopsy to the chance of sperm retrieval in the next testicular sperm extraction (TESE) procedure, we retrospectively analyzed the outcome of past sperm collection procedures and histopathology diagnoses of patients with nonobstructive azoospermia. Repeated TESE ensured a high recovery rate (96%) when the first recovery procedure had been successful and when hypospermatogenesis was diagnosed (77%); when no spermatozoa were found on the first attempt, a repeat TESE procedure was successful in one-third of the patients.

Relationship between nulliparity and preeclampsia may be explained by altered circulating soluble fms-like tyrosine kinase 1

Objective: To test the hypothesis that the risk of preeclampsia in nulliparous women may be due to an anti-angiogenic state. Methods: Maternal serum samples obtained in the third trimester from nulliparous (n = 86) and multiparous (n = 165) singleton uncomplicated pregnancies were analyzed for levels of angiogenic factors – soluble fms like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) by enzyme-linked immunosorbent assay (ELISA). Results: For nulliparous and multiparous pregnancies, serum sFlt1 levels were 12 732 ± 832 and 10 162 ± 666 (p = 0.020), serum PlGF levels were 215 ± 15 and 249 ± 14 (p = 0.093) (all reported as mean SD in pg/ml) and mean ratios of sFlt1/PlGF were 93 ± 12 and 62 ± 5 (p = 0.023), respectively. Adjustment for maternal age and fetal birth weight did not alter the results. Conclusions: Nulliparous pregnancies had higher circulating sFlt1 levels and sFlt1/PlGF ratios than multiparous pregnancies, suggesting an association with an angiogenic imbalance. Taken together with the pathogenic role of anti-angiogenic factors in preeclampsia, our data may be one explanation for the epidemiological observation that nulliparity is a risk factor for the development of preeclampsia.

Ovarian stimulation for oocyte cryopreservation for prevention of age-related fertility loss: one in five is a low responder

Abstract Oocyte cryopreservation for age-related fertility loss is gaining interest considering the tendency to postpone motherhood in many societies. Little is currently known about the actual efficiency of this approach. We aimed to explore ovarian response of presumably fertile women undergoing in vitro fertilization for this indication. A total of 105 women underwent 151 stimulation cycles at mean age 37.7 ± 2.4. None had known infertility. Mean daily starting FSH dose was 371 ± 110 (225–600). Mean number of mature oocytes cryopreserved at the first completed cycle was 9.7 ± 7.5 (0–43). However, 21% of started cycles were either cancelled before egg retrieval or resulted in 0–3 mature oocytes retrieved. Therefore, women considering oocyte cryopreservation for prevention of age-related fertility decline should be encouraged to perform this procedure at younger age than, preferably before 35.

Technical modification of testicular sperm extraction expedites testicular sperm retrieval

OBJECTIVE To determine the predictive value and the quality of supernatant sperm (SS) achieved by a simple laboratory technical modification after testicular sperm extraction (TESE). DESIGN A retrospective analysis. SETTING An IVF unit in a university medical center. PATIENT(S) Azoospermic patients undergoing TESE between January 2001 and December 2006. INTERVENTION(S) Before the mechanical shredding, the testicular specimen in toto was placed in medium. The medium was spun and the pellet resuspended and transferred for SS detection. Then a wet preparation of the testicular tissue was shredded roughly and inspected for tissue sperm (TS) as described. MAIN OUTCOME MEASURE(S) Detection of SS versus TS, fertilization and pregnancy rates (PR) after intracytoplasmic sperm injection (ICSI) with SS versus TS. RESULT(S) The SS was detected in all specimens where TS was eventually found, independent of their testicular pathology. When the supernatant was spermatozoa-negative, no spermatozoa were detected in the tissue. For embryos derived from ICSI the fertilization rate of SS was significantly higher than TS (52% vs. 44%), whereas the PR was comparable. CONCLUSION(S) The SS serves as an excellent predictor of TESE outcome and as a superior source for fertilization. This modified technique enables faster decision of TESE outcome and an easier switch to donor sperm when available.

Tumefactive demyelination following in vitro fertilization (IVF)

Tumefactive demyelination (TD) is a solitary cerebral demyelinating lesion clinically and radiologically mimicking brain tumors. It can occur in isolation or may be rarely associated with other demyelinating diseases. The underlying pathogenic mechanisms are unknown. We present the first report of TD following in-vitro fertilization (IVF) in a 36-year-old healthy woman who developed subacute right hemiparesis shortly after a scheduled IVF cycle. Evaluation revealed left hemispheric space-occupying lesion pathologically diagnosed as TD. Treatment with intravenous methylprednisolone promptly resulted in a clinical and radiological improvement maintained thereafter. This report confirms and expands the spectrum of inflammatory demyelinating conditions associated with IVF and suggests possible hormonal influence in the development of TD.

Acute renal failure may lead to reversible azoospermia.

OBJECTIVE To report a possible association between azoospermia and acute renal failure. DESIGN A case report. SETTING An in vitro fertilization unit in an academic medical center. PATIENT(S) A patient with high-gonadotropin azoospermia and a history of acute obstructive renal failure because of bilateral renal calculi, who was referred for testicular sperm extraction. INTERVENTION(S) Deferral of the surgical procedure. MAIN OUTCOME MEASURE(S) Return of sperm into the patients ejaculate. RESULT(S) Four months after normalization of his renal function tests, the sperm analysis showed reversal of the azoospermic state. CONCLUSION(S) Azoospermic patients with recent history of acute renal failure would be followed up for several months after renal function normalization, awaiting reappearance of sperm in the ejaculate.