Expression profiling of autophagy associated genes in placentas of preeclampsia.

Autophagy, a mechanism of cell survival during times of stress, may be active in normal placental maintenance, cushioning the fetus from strain during fluctuations in nutrient availability. Moreover, in cases of placental insufficiency, often present in preeclampsia, autophagy may be defective. We used published microarray datasets to analyze differential expression of autophagy pathway genes. No statistically significant difference in autophagy associated gene expression was found in preeclamptic vs. normal placenta samples. Thus although preeclampsia displays many of the features suggestive of altered autophagy, impaired placental autophagy as a cause of preeclampsia is not supported by whole placental tissue differential expression profiling.

Human trophectoderm apposition is regulated by interferon γ-induced protein 10 (IP-10) during early implantation.

INTRODUCTION: The first step in human implantation is the attraction of the blastocyst to the endometrium. We aimed to study attraction of the human blastocyst to the endometrium, and how this process is accomplished by chemokines secreted by the endometrium. MATERIALS AND METHODS: Blastocyst trophectoderm cells and other trophoblast lineage cells were subjected to attraction assays by IP-10 and other chemokines using transwell migration and chemotaxis assays. Chemokine expression and secretion were investigated using immunohistochemistry, ELISA, FACS analysis, and RT-PCR on material from flushing of the uterine cavity in endometrial biopsies. Chemokine receptor expression by blastocyst trophectoderm following PGD biopsy, trophectoderm derived from hES, placental villi, and other trophoblast lineage cells were characterized by the same methods. RESULTS: IP-10 dramatically attracted trophectoderm derived from hES cells and other lineages by interaction with CXCR3 chemokine receptors, as shown by both chemotaxis and transwell migration. High levels of IP-10 were detected throughout the menstrual cycle at flushing of the uterine cavity. Immunohistochemistry, FACS analysis, and RT-PCR of endometrial biopsy detected IP-10 in glandular and stromal cells of the endometrium. High levels of IP-10 were detected in condition medium of the endometrial stromal and glandular cells. Of all of the chemokine/chemokine receptor combinations examined, the IP-10/CXCR3 interaction was the only cytokine that was significantly elevated. DISCUSSION: While they await the wandering blastocyst, IP-10 is produced by many cells of the endometrium, but not by endometrial natural killer cells. CONCLUSION: Endometrial IP-10 may specifically attract human blastocyst trophectoderm cells early in implantation.

Reproductive outcome of men with azoospermia due to cryptorchidism using assisted techniques.

The aetiology of cryptorchidism is still undiscernible in the majority of cases. It has long been argued that cryptorchidism reflects a primary testicular maldevelopment, where the contralateral scrotal testis also suffers from aspermatogenesis and low spermatogonia count. The aim of the study was to determine the reproductive outcome of ex-cryptorchid men with azoospermia post-orchidopexy after testicular sperm extraction (TESE) and intracytoplasmatic sperm injection (ICSI). In a retrospective analysis, we compared the sperm retrieval, fertilization, pregnancy and live birth rates after ICSI of consecutive ex-cryptorchid azoospermic patients (n = 15) undergoing TESE between Jan 2000 and Dec 2007 vs. non-cryptorchid azoospermic men (n = 142). Sperm retrieval rate of ex-cryptorchid men by TESE (66%) was comparable with non-cryptorchid men (47%) (p = 0.15) despite significantly higher FSH levels (30.7 +/- 25.4 vs. 17.9 +/- 14.8 respectively) (p = 0.018) and a more prevalent histopathology diagnosis of aspermatogenesis (75% vs. 40%, p = 0.046). Fertilization (43.3%), pregnancy (30%) and live birth (20%) rates after TESE-IVF-ICSI in the ex-cryptorchid group were not different from the non-cryptorchid group (48.7, 43 and 29%, p = 0.26, p = 0.21, p = 0.29 respectively). We conclude that the reproductive outcome of ex-cryptorchid men with azoospermia post-orchidopexy employing TESE-IVF-ICSI is comparable with non-cryptorchid azoospermic men.

Misconceptions about oral contraception pills among adolescents and physicians.

BACKGROUND: Limited access to contraception and poor compliance are the major reasons for unintended pregnancy in adolescence. This study was designed to compare knowledge of the combined oral contraceptive pill (COCP) in teenage users and non-users. We speculated that consultations between COCP users and their physicians would dispel misconceptions. METHODS: A cross-sectional survey was undertaken in public clinics affiliated with an academic center. High school-educated female adolescents aged 14-20 years opting for contraception (n = 254) and Israeli physicians (n = 114) specializing in Obstetrics, Gynecology and Reproductive Endocrinology participated in the study. Information about past or present COCP use and views of the COCP were recorded by employing a ten-question YES/NO self-completion questionnaire, designed by the researchers. RESULTS: The prevalence of incorrect beliefs was exceedingly high in the whole adolescent study group and relatively high among the physicians. The prevalence of incorrect beliefs was comparable between COCP users and non-users, regarding the 10 misconceptions investigated. The duration of COCP use did not influence the prevalence of misconceptions about the pill. Age did not serve as a confounding factor for all misconceptions. CONCLUSIONS: Lack of informative communication between COCP-prescribing physicians and users and mistaken knowledge of the caring physicians may contribute to adolescent ignorance of the COCP. Focusing on adolescent-specific disbeliefs could lead to construction of better educational programs in schools and clinics.

Human placental Hofbauer cells express sprouty proteins: a possible modulating mechanism of villous branching.

The development of the chorionic villous tree into a complex and organized ramified tubular network can be termed branching morphogenesis. Studying the molecular mechanisms involved in this process may contribute to the understanding of pregnancy complications such as preeclampsia. Sprouty (Spry) proteins are important regulators of branching morphogenesis and growth factor signaling. We analyzed the expression of Spry genes in human placenta. RT-PCR and immunohistochemistry were employed to detect placental Spry expression. Quantitative RT-PCR was used to assess the effect of FGF and reduced oxygen fraction on Spry gene expression. Spry 1, 2 and 3 expression was observed in placental tissue from all three trimesters. Our results reveal for the first time that Spry proteins are localized in the stroma of the chorionic villi, adjacent to cytotrophoblasts in areas of villous sprouting. Immunofluorescent double staining with anti-Spry and anti-CD68 confirmed that placental macrophages (Hofbauer cells) express Spry. Reduced oxygen fraction, FGF-4 and FGF-10 stimulated Spry-2 expression. Hofbauer cells also expressed c-Cbl, a protein that interacts with Spry. Placental expression of Spry and c-Cbl implies an important role for Hofbauer cells in placental development, possibly through a mesenchymal-epithelial interaction with trophoblasts. Regulation of Spry-2 expression by FGF-4 and FGF-10 suggests an orchestrated regulatory system that modulates villous branching.

Spontaneous ovarian hyperstimulation syndrome and hyperreactio luteinalis are entities in continuum.

Hyperreactio luteinalis (HL) and spontaneous ovarian hyperstimulation syndrome (OHSS) are both rare conditions during pregnancy. The clinical presentation of HL and OHSS are comparable and both should be differentiated from ovarian carcinoma. We present a case of a 32-year-old woman who was initially seen with markedly enlarged multicystic ovaries and ascites in the 13th week of a spontaneously conceived pregnancy. Ultrasonographic follow-up and magnetic resonance imaging of the ovaries were employed in order to avoid exploratory laparotomy and rule out ovarian carcinoma. The patient received supportive therapy and delivered a healthy child at term. The increasing use of ultrasonography may lead to more frequent findings of multicystic ovaries in spontaneously conceived pregnancies. Making the distinction between HL and spontaneous OHSS in these cases may be difficult though clinically irrelevant as the approach to treatment is similar in both.

Eph and ephrin expression in normal placental development and preeclampsia.

Eph receptors and their ephrin ligands play a fundamental role in embryogenesis. Their functions include cell targeting and angiogenesis. In placental development, trophoblasts migrate and invade maternal tissue and spiral arteries, where they play a role in both anchoring the placenta to the uterus and increasing blood flow to the developing fetus (interstitial and endovascular invasions). We investigated the cellular distribution and expression patterns of representative Eph and ephrin RNA and protein in an effort to identify the molecules involved in trophoblast migration during normal placental development and placental pathologies. We found ephrin-A1 expressed exclusively in the invasive extravillous trophoblast (EVT) cell lineage. We therefore proceeded to investigate ephrin-A1 in placental pathologies with defects in EVT invasion. In preeclampsia, where trophoblast invasion is shallow, we observed ephrin-A1 expression similar to normal placenta. Furthermore, in initial experiments on the deeply invading trophoblasts of placenta accreta, which lacks decidua, ephrin-A1 is found to be expressed highly in extravillous trophoblasts that have invaded the myometrium. In addition, we found the prototype ephrin-A1 receptor, EphA2, localized in several placental cell types. EphB4 and ephrin-B2 molecules, which have specific expression patterns during artery and vein development, respectively, were also expressed in the placenta. The cell specific distribution of ephrin-A1 suggests that it may play a role in targeting and migration of trophoblasts, and in the vascular remodeling induced by the invading extravillous trophoblasts. Failure of ephrin-A1 expression is unlikely to be the primary cause in defective migration of trophoblasts observed in preeclampsia. Specific roles for other Eph and ephrin proteins remain to be investigated.

Conservative management of two ectopic pregnancies implanted in previous uterine scars.

Cesarean section scar pregnancy is rare. A variety of interventions have been implemented to terminate the pregnancy and preserve the uterus; however, the optimal treatment is unknown. We describe two cases of this rare condition diagnosed by transvaginal ultrasound. In the first case the diagnosis of an 8-week non-viable gestation in a uterine scar was made sonographically in a 40-year-old woman. The patient was treated with intramuscular methotrexate. Myometrial integrity was suggested both by ultrasound findings and laparoscopic findings. In the second case, an early cervicoisthmic pregnancy in a uterine scar was diagnosed by sonography in a 39-year-old woman. This patient was treated successfully with a full course of intramuscular methotrexate. Complete disappearance of the gestational sac took place 4 months following beta-human chorionic gonadotrophin normalization. Intramuscular methotrexate may be a treatment alternative for Cesarean section scar pregnancies.

Azoospermia due to testicular amyloidosis in a patient with familial Mediterranean fever.

We describe a patient suffering from familial Mediterranean fever (FMF) who presented to our clinic with secondary infertility of 2 years due to amyloid A amyloidosis. His spermiogram disclosed azoospermia. A testicular biopsy revealed hyalinized tubules devoid of full spermatogenesis and containing abundant amyloid, confirmed by Congo red stain. We suggest that testicular amyloidosis be taken into consideration when dealing with azoospermic FMF patients. In view of the progressive nature of amyloid accumulation in the testis we propose to follow routinely the spermiogram of FMF patients with renal amyloidosis. Furthermore, consideration of sperm cryopreservation is suggested in these cases. In FMF patients with azoospermia consideration of testicular biopsy is recommended as early as possible in order to increase the chance of sperm retrieval.

The effect of colchicine treatment on sperm production and function: a review.

Colchicine is used for the treatment of various diseases including gouty arthritis, familial Mediterranean fever (FMF) and Behcet's disease. As a modulator of the microtubules at the cytoskeleton level, it arrests cell division at metaphase and inhibits microtubular-dependent cell motility. Controversy exists as to the adverse effect of colchicine on sperm production and function in healthy subjects as well as in gout, FMF and Behcet's patients. Sperm analysis shows a spectrum of pathology, from oligo- and azoospermia to normospermia with disturbances in sperm motility. These inconsistent sperm pathologies can be explained in part by the variability of the pathophysiology of the underlying disease. Thus, it seems that colchicine by itself may not have a significant direct adverse effect on sperm production and function.

The contraceptive choice for a Wilson's disease patient with chronic liver disease.

Preserved fertility status is frequently encountered in patients with Wilson's disease, and contraceptive counseling may, therefore, be a relevant issue. Yet, several contraceptive methods can adversely influence the hepatic function, and the efficacy of others may be affected by the liver disease. We describe a patient with Wilson's disease manifested by cirrhosis, portal hypertension, and bleeding esophageal varices who underwent termination of pregnancy at 9 weeks' gestation. Following the procedure, contraceptive advice was sought in order to postpone conception until portal hypertension was controlled and hepatic function improved. Intramuscular depot medroxyprogesterone acetate was administered and tolerated well by the patient. A detailed discussion of the contraceptive options for patients with chronic liver disease, in general, and Wilson's disease, in particular, follows the case report.

PIP: Although the fertility status of women with Wilson's disease may be preserved, contraceptive method choice is complicated by the tendency for some methods to have an adverse effect on hepatic function and, conversely, for liver disease to compromise the efficacy of some contraceptives. This paper presents the case of a 28-year-old woman diagnosed with Wilson's disease at 13 years of age. She presented to an Israeli hospital at 9 weeks' gestational age with bleeding esophageal varices, cirrhosis, and portal hypertension. Although the patient had been oligomenorrheic, with menses every 2-3 months, she had experienced 3 spontaneous first-trimester abortions. Due to the urgent need for a portal decompression shunt procedure and the risk of further bleeding, the patient opted to terminate the current pregnancy. To prevent conception until the patient's liver condition stabilized, she was injected with Depo-Provera and penicillamine treatment was resumed. Although IUDs and estrogen-containing oral contraceptives are relatively contraindicated in women with liver dysfunction, spermicide and barrier contraceptives are highly recommended and progesterone-only preparations can be safely prescribed.