The impact of loop electrosurgical excision procedure (LEEP) for CIN 2,3 on spontaneous preterm delivery in twin pregnancies by assisted reproductive technique: preliminary data.

The objective of this study was to compare the frequency of spontaneous preterm delivery before 35 weeks in 7 dichorionic twin pregnancies obtained after loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia (CIN) 2,3 with respect to 21 twin pregnancies without previous cervical treatment. All the pregnancies were obtained after assisted reproduction techniques (ART). Same age at delivery was observed between two groups (p = 0.81) and none of our twin pregnancies after LEEP had a threatened preterm labor while four controls (19%) underwent a spontaneous preterm delivery (p = 0.35). These preliminary data seem to indicate that LEEP may not be responsible of spontaneous preterm delivery in twin pregnancies subsequent to ART.

Uterine fibroids: pathogenesis and interactions with endometrium and endomyometrial junction.

Uterine leiomyomas (fibroids or myomas) are benign tumors of uterus and clinically apparent in a large part of reproductive aged women. Clinically, they present with a variety of symptoms: excessive menstrual bleeding, dysmenorrhoea and intermenstrual bleeding, chronic pelvic pain, and pressure symptoms such as a sensation of bloatedness, increased urinary frequency, and bowel disturbance. In addition, they may compromise reproductive functions, possibly contributing to subfertility, early pregnancy loss, and later pregnancy complications. Despite the prevalence of this condition, myoma research is underfunded compared to other nonmalignant diseases. To date, several pathogenetic factors such as genetics, microRNA, steroids, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in the development and growth of leiomyoma. This paper summarizes the available literature regarding the ultimate relative knowledge on pathogenesis of uterine fibroids and their interactions with endometrium and subendometrial myometrium.

Complex networks of multiple factors in the pathogenesis of uterine leiomyoma.

OBJECTIVE: To summarize the information regarding pathogenetic factors of leiomyoma formation and growth, and to make a simple integrated pathogenetic view of this tumor for further thinking to establish new therapeutic options. DESIGN: PubMed and Google Scholar searches were conducted to identify the relevant studies on pathogenesis of uterine leiomyoma, which are hereby reviewed and discussed. SETTING: Academic medical center. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Not applicable. RESULT(S): To date, the pathogenesis of uterine leiomyomas is not well understood. However, genetic alterations (especially MED12 and HMGA2) and involvement of epigenetic mechanisms (DNA methylation, histone modifications, and microRNA) in leiomyoma provide the clue of initiator of this tumor. Estrogens and P are considered as promoters of leiomyoma growth, and growth factors, cytokines, and chemokines are thought to be as potential effectors of estrogens and P. Extracellular matrix components are a major structural part of leiomyoma tissue that are abnormally orientated and can modify mechanical stress on cells, which leads to activation of internal mechanical signaling and may contribute to leiomyoma growth. CONCLUSION(S): Besides many genetics and epigenetic factors, the important link among the sex steroids, growth factors, cytokines, chemokines, and extracellular matrix and their involvement in cell proliferation, fibrotic processes, apoptosis, and angiogenesis are implicating a complex network in leiomyoma formation and growth. Those findings could provide information to establish future therapeutic options for the management of this tumor.

Clues to apoptosis pathway involvement in hemolysis, elevated liver enzyme, and low platelet (HELLP) syndrome and intrauterine growth restriction (IUGR).

OBJECTIVE: The neurotrophin family comprises molecules involved in growth, differentiation, survival, regeneration, normal functions of the neuronal system, and in angiogenesis. We have investigated the expression pattern of neurotrophic signaling molecules in pregnancies complicated by elevated liver enzyme, and low platelet (HELLP) syndrome and intrauterine growth restriction (IUGR). METHODS: Placentas from normal and pathological pregnancies were collected. Macroarray analysis was performed and the data were confirmed by real-time PCR. RESULTS: Real-time PCR analyses (pathological vs. normal pregnancies) confirmed a significant down-regulation for IL-6, STAT3α, STAT3ß, and Bcl-2. The expression of Mcl-1 isoform 1 (long) was significantly increased. CONCLUSIONS: We suggest that decreased expression of IL-6 could mean that abnormalities in the immunological system function involve inflammatory cytokines other than IL-6 in examined pathological pregnancies. The STAT3α and STAT3ß down-regulation lead to a marked reduction of cellular transcriptional activity. Decreased expression of IL-6 is associated with a down-regulation of Bcl-2 but not of Mcl-1 isoform 1, suggesting that these two antiapoptotic proteins may function independently and that Mcl-1 may have a distinct role in controlling apoptotic pathway.

The involvement of inflammatory cytokines in the pathogenesis of recurrent miscarriage.

OBJECTIVE: To investigate the inflammatory cytokine expression pattern in trophoblastic tissue from women with unexplained recurrent miscarriage (RM). STUDY DESIGN: Trophoblasts were obtained during uterine evacuation from 11 women with RM and from 20 healthy pregnant women undergoing elective termination of pregnancy, who served as controls. The array was performed using GEArray Q Series Human Inflammatory Cytokines & Receptors Gene Array HS-015 membranes. Data were confirmed by quantitative real-time PCR. The Mann-Whitney U test was performed for statistical analysis. RESULTS: Microarray analysis identified three genes that were differentially expressed between RM patients and controls. We observed significant downregulation of Transforming Growth Factor beta 3 (TGF-ß3) and Interleukin 25 (IL-25) (5-fold reduction and 2.5-fold reduction, respectively) and significant upregulation of CD-25, also known as Interleukin 2 receptor alpha (IL-2RA) (7-fold increase) in women with RM compared with controls. The median ΔC(t) of TGF-ß3 was 8.2 (interquartile range, 7.67-8.9) in RM patients vs. 5.85 (interquartile range, 5.3-6.09) in controls; the median ΔC(t) of IL-25 was 5.18 (interquartile range, 4.46-5.76) in RM patients vs. 3.85 (interquartile range, 3.6-4.51) in controls, and the median ΔC(t) of CD-25 was 9.62 (interquartile range, 7.81-12.42) in RM patients vs. 12.44 (interquartile range, 11.02-13.86) in controls. DISCUSSION: Our results suggest that the immunological and inflammatory regulation mechanisms of the placental environment play a key role in recurrent miscarriage. The observed trophoblast cytokine expression pattern at the maternal-fetal interface confirms the immunotrophic theory, as demonstrated by a switch from a T-helper-1 (Th1) profile to a T-helper-2 (Th2) profile in women who experience recurrent miscarriages.

Placental thrombomodulin expression in recurrent miscarriage.

BACKGROUND: Early pregnancy loss can be associated with trophoblast insufficiency and coagulation defects. Thrombomodulin is an endothelial-associated anticoagulant protein involved in the control of hemostasis and inflammation at the vascular beds and it's also a cofactor of the protein C anticoagulant pathway. DISCUSSION: We evaluate the Thrombomodulin expression in placental tissue from spontaneous recurrent miscarriage and voluntary abortion as controls. Thrombomodulin mRNA was determined using real-time quantitative polymerase chain reaction. Reduced expression levels of thrombomodulin were found in recurrent miscarriage group compared to controls (1.82-fold of reduction), that corresponds to a reduction of 45% (from control group Delta CT) of thrombomodulin expression in spontaneous miscarriage group respect the control groups. SUMMARY: We cannot state at present the exact meaning of a reduced expression of Thrombomodulin in placental tissue. Further studies are needed to elucidate the biological pathway of this important factor in the physiopathology of the trophoblast and in reproductive biology.

Placental Alpha Hemoglobin Stabilizing Protein (AHSP) and recurrent miscarriage.

AHSP inhibits cellular production of the reactive oxygen species. Reduced AHSP indicates reduced protection against oxidative stressors. Our objective was to investigate AHSP levels in recurrent miscarriage (RM). Trophoblast was collected from women of 10 weeks gestation: voluntary abortion controls (VA, n = 10); spontaneous first miscarriage with subsequent normal pregnancy (SMSN, n = 15) or with subsequent miscarriage (SMSM, n = 5); RM previously investigated (RMPS, n = 5) or not previously investigated (RM, n = 5). AHSP mRNA and protein were determined using real-time quantitative polymerase chain reaction (PCR) and Western blot, respectively. One-way ANOVA was performed to assess statistical significance (p < 0.05). ahsp mRNA levels were maximally reduced in RM and RMPS (8.0 x 10(-6) +/- 1.3 and 8.1 x 10(-6) +/- 0.7, respectively) compared with SMSN and VA (16.1 x 10(-6) +/- 2.3 and 26.1 x 10(-6) +/- 2.7, respectively). SMSM showed levels significantly reduced as well (9.0 x 10(-6) +/- 2.3). In RM, a reduced defense from oxidative stressors is evident at first miscarriage, identifying women at high risk for subsequent eventful pregnancy. Reduced AHSP may identify women at risk of experiencing further miscarriages.