Eyal Y. Anteby

Developmental regulation of the expression of 72 and 92 kd type IV collagenases in human trophoblasts: A possible mechanism for control of trophoblast invasion

OBJECTIVE During early pregnancy fetal cytotrophoblast cells invade the uterus and penetrate the basement membrane, a property that is characteristic of malignant cells. However, unlike tumor invasion, trophoblast invasion of the uterus is under strict control. This control limits invasion, so that it primarily remains confined to the endometrial aspect of the myometrium and continues only until midgestation. The invasive properties of the trophoblast cells are made possible by the activity of proteolytic enzymes that belong to the metalloproteinases and serine proteinases. Type IV collagenase (metalloproteinase) is considered crucial in the extracellular matrix remodeling that takes place during the invasion process. In this study we set out to characterize the invasive properties of trophoblast cells at different stages of pregnancy. STUDY DESIGN Human trophoblast cells were isolated from first- and third-trimester placentas by trypsin digestion and Percoll fractionation and were then cultured under serum-free conditions. The invasive ability of trophoblast cells was determined by the in vitro invasion assay, in which the ability of cells to penetrate an artificial basement membrane was examined. Metalloproteinase activity was measured by zymography, and the expression of messenger ribonucleic acid transcripts of 72 and 92 kd type IV collagenases was examined by reverse transcriptase polymerase chain reaction. RESULTS First-trimester trophoblasts were 3.5 time more invasive in vitro than were third-trimester trophoblast cells (p < 0.005). Although first-trimester trophoblasts secreted both species of type IV collagenase, 72 and 92 kd, in large amounts, third-trimester cells secreted the 92 kd and only minimal amounts of 72 kd type IV collagenase. Moreover, first-trimester trophoblasts secreted significantly more (p < 0.05) 92 kd type IV collagenase than did third-trimester trophoblast. The messenger ribonucleic acid transcript expression of 72 and 92 kd type IV collagenases correlated with the activity of these enzymes secreted by first- and third-trimester trophoblasts. CONCLUSION The described high in situ invasive capacity of first-trimester trophoblast might be explained by the increased expression and production of 72 kd type IV collagenase and the higher expression of 92 kd type IV collagenase by first-trimester trophoblast cells.

The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate

OBJECTIVE To assess the deleterious effect of clomiphene citrate (CC) on the development of the endometrium and its improvement by the addition of ethinyl estradiol (E2). PARTICIPATING PATIENTS: Infertility-treated patients, monitored for induction of ovulation or timing of insemination (control group). DESIGN We studied four groups of women during an ovulatory cycle with various treatment schedules. Group 1: untreated patients; group 2: patients treated by CC; group 3: patients treated by CC + ethinyl E2; group 4: patients treated by human menopausal gonadotropin. Follow-up of the patients was done by vaginal ultrasonography and measurements of blood E2. RESULTS In the group treated by CC, both endometrial thickness and uterine volume growth during the follicular phase were lower as compared with untreated controls and menotropin-treated patients. The addition of ethinyl E2 to these patients reversed this deleterious effect of CC without interfering with ovulation. CONCLUSION Ethinyl E2 may reverse the deleterious effect of CC on endometrial development during the follicular phase.

Expression of gelatinase B by trophoblast cells: down-regulation by progesterone.

OBJECTIVE It is now accepted that gelatinase B (92 kd type IV collagenase) is involved in blastocyst implantation and trophoblast invasion. However, little is known about the regulation of this enzyme at the fetomaternal interface. Progesterone has been demonstrated to inhibit gelatinase B secretion from endometrial cells, myometrium, and cervical fibroblasts. Interestingly, the promotor of gelatinase B contains a progesterone-responsive element that may explain transcriptional activation of this metalloproteinase by progesterone. It may be hypothesized that progesterone secreted from trophoblast cells, representing the fetal part of the fetomaternal interface, may have a role in the regulation of gelatinase secretion and blastocyst implantation. STUDY DESIGN To this end, use was made of first-trimester trophoblast cells obtained from first-trimester pregnancy terminations. The trophoblast cells were separated by trypsin degradation and fractionation on Percoll gradients. Metalloproteinase activity was measured by zymography, and the expression of the gelatinase B messenger ribonucleic acid was determined by the solution hybridization/ribonuclease protection assay. RESULTS Primary cell cultures of trophoblasts from first trimesters of pregnancy constitutively elaborated two species of type IV collagenases (gelatinase A and B) as assessed on a gelatin matrix. Treatment with progesterone decreased the accumulation of a gelatinase B species in a dose-dependent fashion. Administration of a progesterone receptor antagonist onapristone (ZK-98.299) neutralized the progesterone inhibitory effect on the gelatinase B in a dose-dependent fashion, thus supporting the presumption that the progesterone effect is receptor mediated. Progesterone significantly attenuated the expression of gelatinase B by trophoblast cells, an effect that was neutralized by ZK-98.299. CONCLUSION These observations provide strong indirect support for the participation of progesterone in the regulation of gelatinase B in trophoblast cells. It may be an important regulator of gelatinase production at the fetomaternal interface.

Route of delivery of fetuses with structural anomalies

Our ability to diagnose fetuses with congenital anomalies has dramatically increased over the past two decades and with improved surgical treatment for some defects, more women may choose to continue their pregnancies. Antenatal management is thus of increasing relevance. The literature on route of delivery suggests the following conclusions. Babies with neural tube defects presenting by the breech benefit from caesarean section but there is no clear evidence that cesarean improves outcome in those with a vertex presentation. When the size of the sac exceeds 6 cm, cesarean section may be justified to decrease the risk of disruption. Vaginal delivery is desirable in all other cases to reduce maternal morbidity. Cystic hygroma: cesarean section offers optimal conditions for management of large anterior lymphangiomas that can obstruct the airway. Sacrococcygeal teratoma: the current approach is based on the size of the tumor. In a fetus with a tumor of less than 5 cm, vaginal delivery may be attempted. Ventral wall defects: there is no conclusive evidence that cesarean section is beneficial for fetuses with omphalocele. Gastroschisis: because of the heterogeneity of the studies, it is difficult to assess the net impact of mode of delivery. There is no evidence of significant differences in outcome among fetuses delivered by the vaginal versus the abdominal route. Trauma to the abdominal viscera can occur during either route, and careful delivery is thus mandated.

The influence of body mass index on in vitro fertilization outcome.

To examine whether body mass index (BMI) influences the outcome of in vitro fertilization (IVF).

Germ cell tumors of the ovary arising after dermoid cyst resection : a long-term follow-up study

Objective: To study the long‐term ovarian neoplastic consequences of resection of a dermoid cyst. Methods: The study population comprised 99 patients who were operated on for an ovarian dermoid cyst. Follow‐up information was obtained for 91 women for a mean period of 5.06 ± 2.46 years. Results: Of the 99 women, 18 had bilateral dermoid cysts. Multiple dermoid cysts in a single ovary were found in nine of the women with bilateral cysts and in one of the remaining patients. Two patients developed malignant germ cell tumors, and three developed a recurrent dermoid cyst in an ovary from which a dermoid cyst had previously been extracted. Bilateral or multiple ovarian dermoid cysts were present at the initial operation in four (80%) of these patients. Conclusions: Women with bilateral or multiple dermoid cysts may include a subgroup of patients with a greater tendency to develop future ovarian germ cell neoplasms. (Obstet Gynecol 1994;83:605‐8)

Substituting HCG with GnRH agonist to trigger final follicular maturation - : a retrospective comparison of three different ovarian stimulation protocols

The study retrospectively evaluated the influence of triggering final oocyte maturation with gonadotrophin-releasing hormone (GnRH) agonist on the outcome of IVF cycles. Four hundred and sixty consecutive women admitted to the IVF unit during a 4-year period were enrolled in the study. Ovarian stimulation characteristics and clinical pregnancy rate were compared between three groups: patients at risk of developing ovarian hyperstimulation syndrome (OHSS), undergoing either the long GnRH-agonist protocol (agonist group) or the flexible multidose GnRH-antagonist protocol who received GnRH-agonist for final oocyte maturation (antagonist-agonist group); and patients not at risk of developing severe OHSS undergoing the flexible multidose GnRH-antagonist protocol who received human chorionic gonadotrophin (HCG) for final oocyte maturation (antagonist-HCG group). Implantation and clinical pregnancy rates were lowest in the antagonist-agonist group despite the fact that no difference were was observed in fertilization rates between the groups. Moreover, the high-responder antagonist-agonist group required shorter stimulation and had higher numbers of oocytes retrieved as compared with the high-responder agonist-group. No case of severe OHSS was observed in the antagonist-agonist group. The use of flexible multidose GnRH-antagonist protocol with GnRH-agonist for final oocyte maturation, in high-responder patients, eliminates the risk of OHSS but results in decreased implantation and pregnancy rates.

GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of endometrial receptivity

To examine whether the choice of the GnRH analogues used during controlled ovarian hyperstimulation (COH), may influence endometrial receptivity, we studied 712 IVF cycles, in patients undergoing COH with GnRH agonist or antagonist and with the transfer of at least one top-quality embryo. The GnRH agonist group showed significantly higher endometrial thickness and higher pregnancy rate, suggestive of a higher endometrial receptivity, compared with the GnRH antagonist group.

Does salpingectomy affect the ipsilateral ovarian response to gonadotropin during in vitro fertilization-embryo transfer cycles?

In a study on the influence of salpingectomy on the same patient ipsilateral ovarian response, 15 patients who were admitted to our department with the diagnosis of uni- or bilateral hydrosalpinges and who were successfully treated by laparoscopic salpingectomy were evaluated. The observed significant decrease in the ipsilateral ovarian response after salgingectomy, as reflected by the quantity of developing follicles during controlled ovarian hyperstimulation for IVF, should be presented to patients during the decision-making process, before offering salpingectomy for the treatment of hydrosalpinx.

Puerperal and Intrapartum Group A Streptococcal Infection

OBJECTIVE: To determine the demographic and clinical variables characteristic of non-epidemic intrapartum or puerperal group A streptococcal (GAS) infection. METHODS: The records of 47 patients diagnosed with intrapartum or puerperal GAS infection over a 6 1/2 year period at Hadassah-University Hospital-Mt. Scopus, Jerusalem were reviewed. Data regarding 25,811 women, the general population of women that delivered during that period, were obtained from their computerized medical records. Frequency distributions, t-test, chi-square, and Spearmans Rank Correlation were used, as appropriate, to analyze and compare demographic and clinical variables associated with development of GAS infection, its clinical course and subsequent development of septic shock. RESULTS: Mean age of mothers with GAS infection was higher than that of our general pregnant population (30.4 versus 27.4 years, P = 0.0019), and a higher proportion of GAS infected patients (30% versus 12%, P < 0.005) experienced PROM. Thirty-one (66%) women had fever as their sole presenting symptom, eight (17%) had fever and abdominal pain, seven (15%) had fever and abnormal vaginal bleeding, and one patient (2%) presented with a rash. Three patients (6%) developed a septic shock. Two of these patients presented with symptoms more than 14 days after delivery. CONCLUSIONS: We describe the characteristics of non-epidemic intrapartum or puerperal GAS infection. Data from our study and review of the literature suggest that some patients who develop septic shock may present later in the puerperium than patients with an uncomplicated GAS infection.