Combined Systemic and Hysteroscopic Intra-Amniotic Injection of Methotrexate Associated with Hysteroscopic Resection for Cervical Pregnancy: A Cutting-Edge Approach for an Uncommon Condition.

This case report of a 36-year-old woman with a diagnosis of cervical pregnancy describes a novel approach to this rare form of ectopic pregnancy, which was successfully treated with systemic and local methotrexate (MTX) therapy combined with hysteroscopic resection. After local and systemic administration of MTX, the patient underwent hysteroscopic resection of the cervical pregnancy using a 27 bipolar resectoscope with a 4-mm loop. The cervical pregnancy was completely treated, and satisfactory hemostasis was achieved with electrocoagulation. The reported case and literature review demonstrate that the combination of systemic and local (hysteroscopic) administration of MTX with hysteroscopic resection could offer the possibility of a safe, successful, minimally invasive, and fertility-sparing surgical treatment for cervical pregnancy.

Uterine Wound Healing: A Complex Process Mediated by Proteins and Peptides.

Wound healing is the process by which a complex cascade of biochemical events is responsible of the repair the damage. In vivo, studies in humans and mice suggest that healing and post-healing heterogeneous behavior of the surgically wounded myometrium is both phenotype and genotype dependent. Uterine wound healing process involves many cells: endothelial cells, neutrophils, monocytes/macrophages, lymphocytes, fibroblasts, myometrial cells as well a stem cell population found in the myometrium, myoSP (side population of myometrial cells). Transforming growth factor beta (TGF-ß) isoforms, connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNF-ß) are involved in the wound healing mechanisms. The increased TGF- ß1/ß3 ratio reduces scarring and fibrosis. The CTGF altered expression may be a factor involved in the abnormal scars formation of low uterine segment after cesarean section and of the formation of uterine dehiscence. The lack of bFGF is involved in the reduction of collagen deposition in the wound site and thicker scabs. The altered expression of TNF-ß, VEGF, and PDGF in human myometrial smooth muscle cells in case of uterine dehiscence, it is implicated in the uterine healing process. The over-and under-expressions of growth factors genes involved in uterine scarring process could represent patient's specific features, increasing the risk of cesarean scar complications.

Pelvic adhesion and gonadotropin-releasing hormone analogue: effects of triptorelin acetate depot on coagulation and fibrinolytic activities.

The study investigated the impact of gonadotropin-releasing hormone analogue (GnRH-a) on coagulation and fibrinolytic activities and its effectiveness in the prevention of pelvic adhesion after myomectomy. Thirty-two infertile women underwent myomectomy followed by adhesion evaluation surgery with a second-look laparoscopy. Before myomectomy, 15 women were treated with triptorelin acetate for 3 months and 17 received no treatment. Plasminogen activator inhibitor (PAI), thrombin activatable fibrinolysis inhibitor (TAFI), protein C (PC), plasminogen, α2-antiplasmin were determined by enzyme-linked immunosorbent assays and the activity of coagulation factors V and VIII by coagulometric methods. Patients treated with GnRH-a showed significant decrease in PAI, TAFI, factors V, and VIII (P < .05) and increased PC (P < .05), but no significant change in plasminogen and α2-antiplasmin levels compared with control group. The incidence, extent, and severity of adhesions were significantly lower in GnRH-a-treated patients compared with control group (P < .05), suggesting a possible critical role of the GnRH-a therapy in preventing postoperative adhesion development.

Leiomyoma pseudocapsule after pre-surgical treatment with gonadotropin-releasing hormone agonists: relationship between clinical features and immunohistochemical changes.

OBJECTIVE: To evaluate if pre-operative GnRH-a modify uterine leiomyoma pseudocapsule and the possible clinical effects of these changes. STUDY DESIGN: The study was performed at the University Federico II of Naples on 33 premenopausal patients submitted to laparotomic myomectomy after treatment with triptorelin depot. 29 untreated patients formed the control group. The operating time, the intraoperative bleeding and the prompt identification of the cleavage plan between myoma and myometrium were evaluated. The pseudocapsule features and the immunoexpression of PCNA and CD34 in this area were studied. RESULTS: Treated patients showed lower blood loss and not clearly identifiable cleavage plan, but without any significant increase in the operating time. Treated lesions showed less evident border between myoma and myometrium and lower PCNA and CD34 pseudocapsule immunoexpression than untreated ones. CONCLUSION: We propose the changes of leiomyoma pseudocapsule as partial explanations of the reported clinical and surgical findings after pre-operative GnRH-a.

Regional and international prenatal telemedicine network for computerized antepartum cardiotocography.

The objective of this work was to review the activity of TOCOMAT, a system for antepartum cardiotocographic telemonitoring. Nine peripheral units recorded the traces, transmitted them via modem to the University operation center, where the computerized analysis was performed, and received the medical report within a few minutes, via fax or e-mail. Traces were classified as reassuring, nonreassuring, or pathological. The parameters of computerized analysis were grouped together for each week of gestation. The perinatal outcome was also evaluated. In 5 years, 5830 traces were analyzed: 4372 (75%) from 1344 high-risk patients and 1458 (25%) from 529 patients at apparent low risk. The system allowed the identification of high-risk patients (32.8% with nonreassuring traces and 7.1% with pathologic traces) and lowrisk patients (16.3% with nonreassuring traces and 4.3% with pathologic traces) that required further evaluation. The neonatal outcome was good overall. At each week of pregnancy, the mean values of computerized parameters resulted in normal ranges. The TOCOMAT system allowed a decentralization of prenatal surveillance and improved the patients quality of life and the level of prenatal care.

Severe secondary postpartum hemorrhage 3 weeks after cesarean section: alternative etiologies of uterine scar non-union.

A case of secondary postpartum hemorrhage that occurred 3 weeks after cesarean section requiring total abdominal hysterectomy is reported. The patient's history and pathologic features of the removed uterus did not allow the authors to clearly recognize a previous reported cause of this potentially life-threatening complication. Alternative causes of the non-union of the uterine incision are suggested.

Four years' experience with antepartum cardiotocography using telemedicine.

We reviewed the first four years of experience with telemonitoring of patients with high-risk pregnancies. Nine peripheral units (eight in Campania, a region of south Italy, and one in Hungary) recorded cardiotocographic traces and transmitted them via modem to an operations centre at the University 'Federico II' in Naples, where the computerized analysis was performed. The medical report was returned to the peripheral unit via fax or email. Four thousand and twenty one traces were recorded: 2674 (67%) from 764 high-risk patients and 1347 (34%) from 499 patients at apparent low risk. The neonatal outcome was good overall. Questionnaires were sent to the operators working at the peripheral units to evaluate the acquisition of specific skills and their level of satisfaction. Sixty-six questionnaires about cardiotocographic trace interpretation were collected. The number of correct answers increased during the study. A total of 33 questionnaires about job satisfaction were collected. The answers showed that the operators gradually overcame their scepticism during the study. A total of 1098 questionnaires were answered by the patients. Their answers showed a moderate level of satisfaction. Telecardiotocography allowed the decentralization of prenatal surveillance.

Preoperative treatment of uterine leiomyomas: clinical findings and expression of transforming growth factor-beta3 and connective tissue growth factor.

OBJECTIVE: To evaluate the clinical features and the expression of transforming growth factor-beta3 (TGF-beta3) and connective tissue growth factor (CTGF) in myometrium and uterine leiomyomas after preoperative treatment with gonadotropin-releasing hormone-analogs (GnRH-a) and tibolone. METHODS: Twenty-three patients received 3.75 mg leuprolide acetate depot for 4 months. Twenty-two patients received the same therapy plus 2.5 mg tibolone daily. Patients underwent uterine surgery after therapy. Twenty-two untreated patients underwent surgery directly. Hematologic tests, bone mineral density (BMD) measurement, and ultrasonographic evaluation of uterine volume were performed before and after treatment. Menorrhagia and pelvic pain were evaluated with a visual analog scale. Hot flushes were recorded in daily diaries. Immunohistochemical expression of TGF-beta3 and CTGF in myometrium and myoma samples was evaluated semiquantitatively. RESULTS: After therapy, hemoglobin and iron levels similarly increased in both groups. BMD significantly decreased only in the GnRH-a group. Uterine volume similarly decreased in both groups. No patient had menorrhagia or pelvic pain at the end of therapy. The number of hot flushes increased after the first month in the GnRH-a group; in the GnRH-a plus tibolone group, it remained constant and was lower. In untreated cases, TGF-beta3 and CTGF smooth muscle cell immunoexpression was lower in myometrium than in leiomyomas. After medical treatment, growth factor immunoexpression remained unchanged in myometrial samples and was reduced in leiomyomas. Endothelial cells showed strong immunopositivity, both in untreated and in treated cases. CONCLUSION: This study focuses on the effects of GnRH-a and tibolone on TGF-beta3 and CTGF expression in myometrium and myomas and supports the hypothesis of a pathogenetic role of these growth factors in uterine fibromatosis.

Uterine dehiscence in term pregnant patients with one previous cesarean delivery: growth factor immunoexpression and collagen content in the scarred lower uterine segment.

OBJECTIVE: This study aimed at investigating the relationship between the occurrence of uterine dehiscence in term pregnant scarred uteri and the presence of altered biochemical behavior of the scarring process. STUDY DESIGN: Collagen content and the expression of transforming growth factor-beta and its isoforms transforming growth factor-beta1 and transforming growth factor-beta3, connective tissue growth factor, basic fibroblast growth factor, vascular endothelial growth factor, platelet-derived growth factor, and tumor necrosis factor-alpha in myometrium of lower uterine segment were assessed in 19 otherwise healthy term patients with one previous cesarean delivery who were not in labor. We were searching for differences between patients who showed uterine dehiscence (9 cases) and patients who showed a normal-appearing scarred lower uterine segment (10 cases). We also evaluated all these features in lower uterine segment from unscarred uteri of 10 otherwise healthy patients who were not in labor. RESULTS: In the case of uterine dehiscence, the scarred lower uterine segment showed a higher collagen content, a reduction of pan transforming growth factor-beta expression because of a marked decrease or absence of transforming growth factor-beta3, a reduction of connective tissue growth factor, an increase in basic fibroblast growth factor and a slight enhancement in vascular endothelial growth factor, platelet-derived growth factor, and tumor necrosis factor-alpha expression. CONCLUSION: These findings contribute to meliorate our knowledge about uterine scar healing and allow us to hypothesize that uterine dehiscence of a scarred uterus may be related to altered biochemical behavior of the scarring process.

Antepartum cardiotocography: a study of fetal reactivity in frequency domain.

Cardiotocography (CTG) is the most widely used diagnostic technique in clinical practice to monitor fetal health. Cardiotocographic recording also permits to assess maturation of the fetal autonomous nervous system (ANS): fetal heart rate (FHR) modifications may reveal ANS' reactions to stimuli. To assess fetal reactivity, physicians evaluate specific clinical CTG parameters, generally, by means of visual inspection, thus depending on observer's expertise, with lack of reproducibility. Still nowadays, there is a very high intra- and inter-observer variation in the assessment of FHR patterns. More objective methods for CTG interpretation are of crucial importance. For adults, frequency analysis of heart rate variability (HRV) is a non-invasive and powerful method to investigate ANS activity. This frequency analysis can also be a valid support for a better knowledge of fetal ANS functional state and reactions. Indeed, fetal HRV is a good indicator of fetal well-being in non-stress conditions. Fetal reactivity is a very important CTG characteristic used to diagnose fetal distress, but its interpretation is still uncertain. The aim of this study is to characterise fetal reactivity proposing new fetal HRV frequency parameters to support a more exhaustive CTG analysis.

Erythropoietin and erythropoietin receptor system in a large uterine myoma of a patient with myomatous erythrocytosis syndrome: possible relationship with the pathogenesis of unusual tumor size.

The rare condition of women with erythrocytosis and a concurrent myomatous uterus has been classified as "myomatous erythrocytosis syndrome". Substantial myoma size has been noted as a common denominator in this condition in which recent evidence have confirmed erythropoietin (Epo) production by myoma tissues themselves. Apart from its primary endocrine role in controlling erythropoiesis, Epo has been demonstrated to mediate several cellular processes such as angiogenesis, mitogenesis, and inhibition of apoptosis by autocrine and paracrine mechanisms. Recently, Epo and its receptor (Epo-R) have been shown to be involved in the growth, viability, and angiogenesis of several malignant tumors including human female reproductive organ malignancies. In this paper, we researched on Epo and, as a first in the literature, Epo-R immunoexpression in a large uterine myoma of a term pregnant patient suffering from the myomatous erythrocytosis syndrome. Eight nongravidic leiomyomas and 8 gravidic leiomyomas were used as control group samples. Apart from confirming Epo production by myoma smooth muscle cells in the myomatous erythrocytosis syndrome, we reveal in this pathologic condition a characteristic strong Epo-R expression in myoma endothelial cells and a weak and sporadic Epo-R expression in myoma smooth muscle cells. The striking presence of Epo-R within myoma tissues in the case of the myomatous erythrocytosis syndrome allows us to speculate that myoma Epo production, besides determining erythrocytosis through systemic effects, may contribute, acting by autocrine and paracrine mechanisms, in determining the large myoma size almost always observed in this condition. Finally, we confirm a less but specific immunostaining for Epo in uterine myomas of patients without erythrocytosis and, as a first in the literature, we prove a weak and sporadic Epo-R expression in these lesions. These last results may contribute to knowledge of the yet unclear etiopathogenesis of the most common human gynecologic neoplasm.

Clinical response, vascular change, and angiogenesis in gonadotropin-releasing hormone analogue-treated women with uterine myomas.

OBJECTIVE: Basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) are involved in the pathogenesis of leiomyomas and influence angiogenesis, which is necessary for growth of leiomyomas. Gonadotropin-releasing hormone analogue (GnRH-a) treatment might modify the growth factor expression and the blood supply in myomas. We investigated the effects of GnRH-a treatment on some clinical parameters, on the immunohistochemical expression of bFGF, VEGF, and PDGF, and on the vasculature of leiomyomas. METHODS: Thirty-one women were treated with leuprolide acetate for 3 months; 55 untreated patients formed the control group. Hematologic parameters were assessed at the admission, after GnRH-a treatment, and after surgery. Uterine volume was evaluated by ultrasonography. The immunoexpression of bFGF, VEGF, and PDGF and of the endothelial markers CD34 and CD105, as well as the vascular pattern, were studied in leiomyomas, comparing treated and untreated patients. RESULTS: Hematologic parameters improved and uterine volumes decreased after GnRH-a treatment. The immunoexpression of bFGF, VEGF, and PDGF decreased in treated myomas, together with the total number of vessels and the angiogenetic vessels. CONCLUSION: This study confirms the clinical response of uterine shrinkage after GnRH-a treatment. A pathogenetic role of bFGF, VEGF, and PDGF in myoma growth and vascularization is suggested. Finally, this study indirectly confirms the importance of the vasculature in leiomyoma growth.

Preoperative administration of GnRH-a plus tibolone to premenopausal women with uterine fibroids: evaluation of the clinical response, the immunohistochemical expression of PDGF, bFGF and VEGF and the vascular pattern.

Aim of the study is to compare the effects of preoperative therapy with tibolone plus gonadotropin-releasing hormone analogue (GnRH-a) in premenopausal women with those of GnRH-a alone on clinical response, uterine volume, immunohistochemical expression of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and vascular features of myomas. Seventy women with symptomatic uterine fibromatosis were treated for four months with leuprorelin acetate alone or plus tibolone. Untreated patients were submitted to uterine surgery directly. Uterine volume, hematological data, BMD, myoma-related symptoms and hot flushes were evaluated at the admission and before surgery. Immunohistochemical expression of PDGF, bFGF and VEGF, vascular changes and CD105 expression, as a marker of angiogenesis, were evaluated in myomas obtained after surgery. Uterine volume and myoma-related symptoms reduced and hematological variables increased in treated patients. BMD decreased in patients treated with GnRH-a alone. Hot flushes were less in GnRH-a plus tibolone group than in GnRH-a group. Immunohistochemical expression of PDGF, bFGF and VEGF, vascularization and angiogenesis reduced in treated patients in comparison with untreated ones. In conclusion, the administration of tibolone plus GnRH-a before uterine surgery does not change the clinical and immunohistochemical effects of GnRH-a alone.

A cost study of prenatal telemedicine.

We calculated the cost of using a telemedicine system for the cardiotocographic (CTG) recording of fetal heart rate. In a one-year study in the Campania region of Italy, 162 patients were monitored. The total cost of the telemedicine system was euro;344796. A control group was retrospectively drawn from all deliveries at the university hospital in Naples during the year 2000. Patients were retrospectively assigned to a category of high or low risk, and the hospital costs of the high-risk patients were compared. In the intervention group, 11 of the 87 high-risk patients (13%) were admitted to hospital prematurely, and stayed on average 12 days. In the control group, 203 of the 813 women in the high-risk group (25%) were admitted to hospital prematurely, and stayed on average 20 days. If the women in the control group had been monitored, there would have been a notional saving, through avoided bed days, amounting to 358280, which was similar to the cost of the telemedicine system. The study suggests that the use of telemedicine in CTG monitoring improves the quality of prenatal care.

Collagen content and growth factor immunoexpression in uterine lower segment of type IA osteogenesis imperfecta: Relationship with recurrent uterine rupture in pregnancy.

OBJECTIVE: The purpose of this study was to evaluate collagen content and platelet-derived growth factor, vascular endothelial growth factor, and connective tissue growth factor expression in the myometrium of the uterine lower segment from a patient with type IA osteogenesis imperfecta with recurrent uterine rupture and to evaluate the existence of a relationship between the rare recurrent uterine rupture and the tissue disorders of type IA osteogenesis imperfecta. STUDY DESIGN: Collagen content and platelet-derived growth factor, vascular endothelial growth factor, and connective tissue growth factor expression in the uterine lower segment were assessed in the patient with type IA osteogenesis imperfecta and in eight otherwise healthy ("control") patients. RESULTS: Type IA osteogenesis imperfecta contained less total collagen amount, with no difference in type III collagen expression and showed increased levels of platelet-derived growth factor and vascular endothelial growth factor in myometrial smooth muscle cells. No difference was observed in connective tissue growth factor expression. CONCLUSION: These findings confirm the diminished collagen amount in myometrium from osteogenesis imperfecta and show the presence of additional pathogenetic mechanisms. A relationship is hypothesized between the underlying myometrial biochemical modifications and the recurrent uterine rupture.

Immunohistochemical detection of insulin-like growth factor type I receptor and uterine volume changes in gonadotropin-releasing hormone analog-treated uterine leiomyomas.

OBJECTIVE: This study was undertaken to assess the relationship between insulin-like growth factor (IGF) type I receptor (IGF-I-R) expression in uterine leiomyomas after gonadotropin-releasing hormone (GnRH) analog administration and modifications in uterine size. STUDY DESIGN: Forty-six women with menorrhagia for uterine leiomyomatosis were treated monthly with leuprolide acetate depot 3.75 mg before undergoing surgery. The uterine volume before and after therapy was assessed by transabdominal ultrasonography. Immunohistochemical detection of IGF-I-R was performed on leiomyoma tissue samples. The relationship between IGF-I-R levels and uterine volume changes was analyzed. RESULTS: Uterine volume decreased after therapy. Patients with a lower immunohistochemical expression of IGF-I-R showed a larger decrease in uterine size. CONCLUSION: The shrinkage in uterine volume induced by GnRH analogs seems to be related to the observed reduction in IGF-I-R levels. So, the IGF-I/IGF-I-R system might be involved in leiomyoma growth, and the pharmacologic action of GnRH analogs on uterine leiomyomas might also be related to the effects on IGF-I-R expression.

Conventional and computerized antepartum telecardiotocography. Experienced and inexperienced observers versus computerized analysis.

The study assessed the agreement in cardiotocogram interpretation between the 2CTG computerized system and experienced and inexperienced observers involved in a telecardiotocography project called 'TOCOMAT'. Both observers and computer analyzed FHR baseline, FHR variability, and number of large accelerations and of decelerations. The k coefficient was calculated for the statistical analysis. The interobserver agreement about the evaluation of the FHR baseline and of the large accelerations was good; it was poor about the assessment of the FHR variability and the decelerations. Similar results were obtained for the agreement among observers and computer. The use of a computerized system provides exact values for most CTG parameters; the experts, however, should rely both on clinical features and on the computerized interpretation, to make decisions about management.

Prenatal telemedicine: clinical experience with conventional and computerised antepartum telecardiotocography.

OBJECTIVE: To describe the clinical results of the first working year of a telemedicine project based on computerised telecardiotocography. STUDY DESIGN: The project is based on the "TOCOMAT" system, which remotely recorded and processed cardiotocograms performed at five peripheral units from high and low risk patients, then transferred them to a University Operative Centre, where they were displayed, stored and analysed by the 2CTG system and by two expert observers. RESULTS: 457 traces were analysed. The perinatal outcome was good, except for two high-risk fetuses. Both patients and carers had favourable reactions. The management of patients with pregnancies at risk was improved by the interaction of the physicians involved with the experts at the Operative Centre. CONCLUSIONS: Telemedicine could enable the decentralization of perinatal surveillance, improving quality of life for pregnant and newborn and rationalizing costs for prenatal care.

Relationship between platelet-derived growth factor expression in leiomyomas and uterine volume changes after gonadotropin-releasing hormone agonist treatment.

The unopposed estrogen effect is the main cause of leiomyoma growth and is at the basis of the clinical use of gonadotropin-releasing hormone (GnRH) agonists. Platelet-derived growth factor (PDGF) has been indicated as the main growth factor involved, in vitro in the proliferation response of leiomyoma smooth muscle cells to estrogen stimulation. The aim of this article is to evaluate the mitogenic action of PDGF in vivo by studying the relationship between PDGF expression in leiomyomas and post-GnRH analogue treatment changes in uterine volume. Thirty-nine patients suffering from uterine leiomyomas were treated with leuprorelin acetate depot 3.75 mg for three cycles; 31 untreated patients were enrolled as control group. Uterine volume was determined twice by ultrasonography in each patient, the first time at admission and the second time after treatment in the study group and after 3 months in the control group. The change in the uterine volume was then evaluated. Patients underwent surgery, and PDGF immunohistochemical detection was performed on the obtained fibroid samples. Uterine volume decreased significantly after treatment, whereas just a poor modification was found in the controls. The decrease in the uterine volume was found to be statistically related to PDGF expression. Thus PDGF levels decreased in treated patients as compared with controls. The decreased PDGF production in leiomyomas after GnRH analogue treatment and the relationship between decreased PDGF expression and greater shrink age in uterine volume suggest that PDGF might have a mitogenic action on leiomyomas in vivo.