Conventional fascial technique versus mesh repair for advanced pelvic organ prolapse: Analysis of recurrences in treated and untreated compartments.

117 women with severe pelvic organ prolapse (POP; stage > 2) were enrolled to elucidate a 24-month outcome of POP surgery, using conventional or mesh repair with 3 techniques. 59 patients underwent conventional repair and 58 underwent mesh repair. Two types of mesh were used: a trocar-guided transobturator polypropylene (Avaulta, Bard Inc.) and a porcine dermis mesh (Pelvisoft, Bard Inc.). Women with recurrences, who underwent previous unsuccessful conventional repair, were randomised. Primary outcome was the evaluation of anatomic failures (prolapse stage > 1) in treated and untreated compartments. Anatomic failure was observed in 11 of 58 patients (19%; CI 8.9-29) in the mesh group and in 16 of 59 patients (27.1%; p value = 0.3) in the conventional group. 9 of 11 failures in the mesh group (15.5%; CI 6.2-24.8) were observed in the untreated compartment (de novo recurrences), 14.3% in Pelvisoft and 16.7% in Avaulta arm, while only 1 recurrence in the untreated compartment (1.7%) was observed in the conventional group (odds ratio 10.6, p = 0.03).

Potential benefit of dehydroepiandrosterone supplementation for infertile but not poor responder patients in a IVF program.

AIM: The aim of this paper was to evaluate the hypothesis that pretreatment with dehydroepiandrosterone (DEHA) may improve the result on in vitro fertilization (IVF) and the pregnancy outcome among infertile women with normal ovarian reserve. METHODS: Double-blind, randomized, placebo-controlled study; 52 infertile patients received the long protocol IVF. Patients in Group 1, received 75 mg of DHEA once a day, 8 weeks before starting the IVF cycle and during treatment; control group (Group 2) received placebo. The primary endpoint was pregnancy, live birth and miscarriage rates, secondary endpoint was standard IVF parameters such us stimulation duration (hCG day), E2 on HCG-day, endometrial thickness, number of retrieved oocytes, metaphase II oocytes, embryos transferred and score of leading embryos transferred. RESULTS: Patients in the DHEA group had a significantly higher live birth rate compared with controls (P<0.05). Miscarriage rate was higher in control group (P<0.05). CONCLUSION: DHEA supplementation could have a beneficial effect on IVF outcome in infertile women with normal ovarian reserve.

Pivotal points in interstitial pregnancy: new insights in conservative medical treatment of non-ruptured interstitial pregnancy.

We report the efficacy of a minimally invasive approach of the multidose protocol with methotrexate (MTX) in the management of three cases of interstitial pregnancy (IP), with elevated serum ß-hCG in two cases. New considerations and management strategies are discussed. Successful termination of IP and in one case, a subsequent successful pregnancy, was achieved. The process led to the development of an enhanced understanding of diagnostic modalities and their limitations, with regard to the particular entities under discussion. We also focused attention on pivotal points and anatomical features in the management of this dangerous occurrence. Long-term results with careful follow-up were analysed by instrumental procedure. This hazardous type of ectopic pregnancy can be managed with systemic administration of MTX, also in patients with elevated ß-hCG values. The present report underlines that an integrated approach in early diagnosis, multidose treatment and close follow-up, are essential forms of medical management.

[Clinical function of estrogen receptors in endometrial cancer]. / Recettori di estrogeni nel carcinomaendometriale: significato fisiopatologico e clinico.

Approximately 70-80% of endometrial carcinomas, type I carcinomas, are associated with endometrial hyperplasia, hyperestrogenism, and expression of estrogen receptor (ER). The aim of this review was to clarify the role of ER in endometrial diseases carcinoma. The estrogens exert their effect via two estrogen receptor: α and ß. The ERs modulate transcriptional process by binding directly to the estrogen response elements (ERE) located in the target gene, or in non classical mode through protein-protein tethering with other transcription factors. There are also orphan receptors (their natural ligands have not been identified). Among this group, estrogen receptor-related receptors (ERRs) were identified by their sequences similar to those of ERs. Since the ERRs have shown a high similarity in DNA binding domain with ERs can interfere with estrogen signalling strengthening the hypothesis of an estrogen-ER-ERR crosstalk. Recently, the ERs and estrogen enzymes emerge as pharmacological targets in different disorders, as well as ERRs, and they may represent the reliable biomarkers in endometrial disease.

Endometriosis is characterized by an impaired localization of laminin-5 and alpha3beta1 integrin receptor.

Endometriosis is an estrogen-correlated benign disease characterized by a marked ability of endometrial-like cells to invade and proliferate outside uterine cavity, resembling for some invasive aspect the cancer growth. The molecular mechanisms regulating endometrial cell invasiveness are mostly unknown, although interactions between extracellular matrix (ECM) proteins and their transmembrane receptors, integrins, are likely to play a central role. In particular, laminin (Ln)-5 could be closely involved, as it is in cancer. We have investigated the expression of Ln-1, Ln-5, and collagen IV (Coll IV) ECM proteins and their receptors, alpha3beta1 and alpha6beta4 integrins, in atrophic, proliferative, and secretive endometrium and in endometriosis. The results show that Ln-5, but not Ln-I and Coll IV, is altered in secretive endometrium as well as in endometriosis tissues. No alterations are observed in atrophic or proliferative endometrium. Consistently, the polarization of both integrin subunits alpha3 and beta1, but not alpha6 and beta4, is altered in secretive endometrium and endometriosis tissues, but not in atrophic and proliferative endometrium. These results seem to suggest that Ln-5 and alpha3beta1 could be involved in the invasive mechanism of endometriosis. The altered expression of Ln-5, by upregulating matrix metalloproteases activity, suggest an invading process similar to that of many cancer processes.

A case of Sertoli-Leydig cell tumor in a postmenopausal woman.

Sertoli-Leydig cell tumor belongs to the group of sex cord-stromal tumors of the ovary. These neoplasms account for less than 0.5% of all ovarian tumors and are more often encountered in young women between the ages of 20 and 30 years who usually become virilized. We described an unusual case of Sertoli-Leydig cell tumor in a postmenopausal women who presented with a solid right pelvic mass, a large amount of ascites, and laboratory tests revealing an elevated CA125, all suggesting a pelvic malignancy. Although five similar cases of postmenopausal women with Sertoli-Leydig cell tumor of ovary have been reported in the literature, we believe that this is an useful addition to the literature.

Receptorial and mitochondrial apoptotic pathways in normal and neoplastic human endometrium.

Under normal conditions, in human endometrium, apoptotic and antiapoptotic factors play an important role in tissue homeostasis. Abnormalities of apoptosis, a process implicated in several events in the reproductive organs, may contribute to neoplastic transformation. The present study aimed to investigate the involvement of both the receptorial and the mitochondrial pathways of apoptosis in normal endometrium and in endometrial carcinoma, by measuring caspase-3 and caspase-8 activities and cytosolic cytochrome c levels. Twelve endometrial carcinomas and nine normal endometrial specimens (four in mild proliferative phase, five in late secretory phase) were included in this study. Cytosolic fractions, obtained by differential centrifugation of tissue homogenates, were analyzed for caspase-3 and caspase-8 activities, as well as for cytochrome c content. Caspase-8 activity in normal secretory phase endometrium was higher than that in the proliferative phase and in the endometrial carcinoma. Moreover, higher cytochrome c levels were detected in endometrial carcinoma with respect to normal secretive endometrium. No significant differences were found in caspase-3 activity between normal and pathologic endometrium. The results obtained suggest that in normal endometrium, apoptosis takes place through the activation of both receptorial and mitochondrial pathways. Defects in both these pathways may contribute to the development of endometrial carcinoma.

Polycystic ovary syndrome and cardiovascular disease.

The aim of the present paper is to analyze recent literature concerning the incidence of cardiovascular complications in women suffering from polycystic ovary syndrome (PCOS). The study takes into consideration all the studies that have been published to date in the international literature in order to clarify whether or not PCOS is able to determine an early onset or whether it is responsible for a higher global incidence of cardiovascular complications in adult age. The main difficulty lies in the absence of prospective studies owing to the long period of time existing between the diagnosis of PCOS and cardiovascular disease which notoriously has a long latency period. Much attention has been paid in the literature, on the other hand, to the analysis of the incidence of cardiovascular risk factors in women suffering from PCOS. Although epidemiological studies have not evidenced an increased incidence of death from cardiovascular events in women suffering from PCOS, the above conclusions might well be invalidated by a patient selection bias, by obsolete diagnostic criteria or by medical or surgical therapies that could influence the outcome of the disease and which are not considered as a confusion factor. Undoubtedly, all the data available up to the present suggest that PCOS possesses the intrinsic conditions that lead to an increased incidence of factors predisposing to cardiovascular diseases. Future longitudinal studies of a prospective nature might be useful for understanding whether the higher incidence of predisposing factors might also lead to greater expectation of cardiovascular events or whether medical therapies or other factors (improvement in endocrine symptomatology with the menopause?) may prevent the increase in the expected incidence of these events.

Chemoradiation: A new approach for the treatment of cervical cancer.

Despite advances in screening, cervical cancer remains a major health problem worldwide. In an effort to improve loco-regional control, both neoadjuvant and chemoradiation have been trialed. Recently, five randomized clinical trials performed by the Gynecologic Oncology Group, the Radiation Therapy Oncology Group and the Southwest Oncology Group have demonstrated a significant advantage both in progression-free and overall survival when cisplatin-based chemotherapy was administered during radiation for advanced stages of cervical cancer. Based on the results of these trials, the US National Cancer Institute released a Clinical Announcement supporting the concurrent use of cisplatin-based chemotherapy with radiation therapy for high-risk early stage and locally advanced stage cervical cancer. Subsequently, an additional prospective randomized trial performed by the National Cancer Institute of Canada was not able to show benefit with the use of chemoradiation compared with radiation alone for patients with locally advanced stage cervical cancer. This article will analyze these six clinical trials in order to determine the role of chemoradiation in the management of patients with cervical cancer. Furthermore, as anemia is one of the most powerful prognostic factors in patients with cervical cancer, we propose to evaluate the relationship between a decreased level of hemoglobin and treatment outcome.

Evaluation of functional ovarian reserve in 60 patients.

Diminished ovarian reserve is a condition occurring in women at any adult age, although it is more frequent in women in their 30s and in couples with unexplained subfertility. Different tests are employed to diagnose the problem. The most common are basal tests for FSH, LH, oestradiol and inhibin B, or dynamic endocrine tests such as the clomiphene citrate challenge test and gonadotrophin analogue stimulating test. In recent years, great attention has been devoted to direct tests such as the antral follicle count and ovarian biopsy results. The basal FSH concentration is the most common test utilized for ovarian screening. An abnormal value is correlated with a decrease in pregnancy rate and an increase in cycle cancellation rate. Among other basal endocrine tests, inhibin concentrations appear promising, although more data are necessary before this can be included in clinical practice. The clomiphene citrate challenge test can unmask patients who might have not been detected by basal FSH screening alone, and appears to be more sensitive than day 3 FSH alone. A prospective study was performed on the simultaneous application of various markers of ovarian reserve (FSH, LH, oestradiol, inhibin B, antral follicle count) in the natural cycle preceding assisted reproductive therapy, in 60 women. The present study suggests that counting ovarian follicles by ultrasound appears, at the moment, the most reliable test of ovarian reserve, although it is influenced by subjective factors and more studies are needed in order to confirm its predictive value.

The ultrasound assessment of adipose tissue deposition in fetuses of "well controlled" insulin-dependent diabetic pregnancies.

OBJECTIVE: To assess differences in adipose deposition in fetuses from normal pregnancies and women with diabetes. RESEARCH DESIGN AND METHODS: The study group consisted of 15 well controlled insulin-dependent women with diabetes and 16 controls with a normal glucose. Ultrasound measurements were taken of subcuticular tissue thickness at the abdominal and suprascapular level at 31 and 37 weeks gestation. Triceps and subscapular skinfold thickness were also measured at birth. RESULTS: Gestational age at delivery and birthweights were not significantly different. At 31 weeks, fasting glucose levels were 5.0 +/- 1 mmol/l for diabetic vs. 3.3 +/- 0.3 mmol/l for controls (P < 0.01), post-prandial 5.6 +/- 0.4 vs. 5.1 +/- 0.3 mmol/l (P < 0.01). At 37 weeks, they were 4.6 +/- 0.2 mmol/l vs. 3.8 +/- 1.1 mmol/l (P < 0.01) and 6.0 +/- 0.6 mmol/l vs. 5.3 +/- 0.3 mmol/l (P < 0.01). Abdominal and suprascapular subcuticular thickness were 4.4 +/- 0.1 mm vs. 3.7 +/- 0.1 mm (P < 0.05) and 4.3 +/- 0.2 mm vs. 3.5 +/- 0.2 mm (P < 0.05) at 31; 5.6 +/- 0.2 mm vs. 4.8 +/- 0.1 mm (P < 0.05) and 5.4 +/- 0.2 mm vs. 4.4 +/- 0.1 mm (P < 0.05) at 37 weeks. At birth, triceps and suprascapular skinfolds were 4.7 +/- 0.1 mm vs. 4.1 +/- 0.1 mm (P < 0.05) and 4.7 +/- 0.2 mm vs. 3.8 +/- 0.1 mm (P < 0.01). CONCLUSION: Adipose tissue disposition is increased in fetuses of women with well-controlled diabetes. This may be a reflection of higher maternal glucose levels in these women and may explain why even well-controlled diabetic pregnancies are at risk of macrosomia.

Ultra short-term antimicrobial prophylaxis in patients undergoing surgery for gynecologic cancer.

OBJECTIVE: To evaluate the efficacy of ultra short-term antimicrobial prophylaxis with ceftazidime in patients undergoing radical gynecologic surgery. PATIENTS AND METHODS: Two hundred patients undergoing surgery for a malignant disease of the female genital tract were enrolled in a prospective trial to receive 2.0 g ceftazidime as a single dose, 30 minutes before induction of anaesthesia. After surgery, each patient was assessed to confirm febrile status and the presence of infections at the surgical site, urinary tract and respiratory tract. RESULTS: Postoperative morbidity occurred in 23 patients (11, 5%). Ten patients (5%) developed febrile morbidity, five (2, 5%) vaginal cuff infections, four asymptomatic bacteriuria and two each wound infiltration and urinary tract infection. Twelve patients had microbiological evidence of infection and Staphylococccus aureus was the most common pathogen isolated. Univariate analysis demonstrated that pre-existing systemic disease, extensive blood loss (more than 500 ml) and long duration of surgery (more than 150 minutes) were the only factors associated with a significant increase in postoperative febrile morbidity. CONCLUSIONS: Ultra short-term antimicrobial prophylaxis with ceftazidime is safe and effective in patients undergoing surgery for gynecologic cancer.

Distant metastases in ovarian carcinoma.

Distant metastases are unusual at presentation and during the course of ovarian carcinoma. The aim of the present study was to determine the incidence and prognostic factors of distant metastases consistent with stage IV disease in ovarian cancer patients. A retrospective chart review was conducted on 162 patients with epithelial ovarian carcinoma treated at our Unit between 1991 and 2000. Pertinent clinical information, pathologic data, treatment, and prognostic factors for survival following documentation of distant metastatic disease were collected. The significance of the association between metastatic status and various clinical variables was assessed using the standard chi-square test. Survival time was calculated from the time of diagnosis of ovarian cancer and from the time of diagnosis of the distant metastases. A logistic regression procedure was used to estimate the odds of metastatic status given the presence of certain clinical variables. A total of 67 metastatic sites were diagnosed in 50 patients. Thirteen patients (8%) had distant metastatic disease at the time of diagnosis, 37 patients (22%) had distant metastases at the time of recurrent of progressive disease. Site of metastases were: liver, 21; pleura, 11; lung, 8; central nervous system and skin, 7 each; extra-abdominal lymph nodes and spleen, 5 each; bone, 2; and breast, 1. Significant risk factors for the development of distant metastases were stage, grade, and lymph node involvement. Median interval time between diagnosis of ovarian cancer and documentation of metastatic disease was 44 months (range 3-105), and at the time of diagnosis of distant disease, 36 of 50 patients (72%) had other sites of disease (intra-abdominal or extra-abdominal). Median survival from diagnosis of distant disease was 12 months (range 1-58). In univariate analysis performance status (P = 0.03), the presence of other sites of disease (P = 0.04) and interval time between diagnosis of ovarian cancer and documentation of distant metases (P = 0.03) were the only factors significantly associated with survival. Long interval time remained significant for prognosis in multivariate analysis also (P = 0.04). Distant metastasis consistent with stage IV disease is a late complication that occurs in about one third of ovarian cancer patients. Prognosis after documentation of distant metastases is poor. We conclude the most important prognostic factor associated with survival is the interval time between diagnosis of ovarian cancer and documentation of distant metastases.

Hysteroscopy does not increase the risk of microscopic extrauterine spread in endometrial carcinoma.

Fluid hysteroscopy has been suspected to cause tumor dissemination in the abdominal cavity in endometrial cancer patients. The aim of our study was to evaluate the incidence of microscopic extrauterine spread according to diagnostic modality (dilatation & curretage, D&C, hysteroscopy, or both) in patients with endometrial carcinoma. A retrospective study was conducted on 147 patients with histologically proven diagnosis of endometrial carcinoma without macroscopic extrauterine disease. Fluid hysteroscopy was performed by using saline solution irrigated at a final flow of 150 ml/min with a intrauterine pressure ranging between 25 and 50 mmHg. Microscopic intraperitoneal disease and positive peritoneal cytology were considered the primary end-points of this analysis. Fifty-two patients (35%) had diagnosis of endometrial cancer made only by D&C, 56 (39%) underwent D&C and then hysteroscopy, and 39 (26%) had only hysteroscopy. Distribution of the patients in this three groups was casual, and clinicopathologic characteristics of the patients in the three groups were similar. Peritoneal cytology was positive in nine patients, 13 had microscopic ovarian metastases, and eight had microscopic involvement of the pelvic peritoneum or of omentum. Neither the presence of positive peritoneal cytology nor the findings of microscopic intraperitoneal dissemination were significantly associated with the diagnostic procedure employed for primary diagnosis (D&C or D&C plus hysteroscopy or hysteroscopy alone). We conclude that fluid hysteroscopy does not increase the risk of microscopic intraperitoneal spread in endometrial cancer patients as compared to D&C.

Intratumoral blood flow characteristics and prognostic factors in patients with endometrial carcinoma.

Purposes of the study were to evaluate the correlation between intratumoral blood flow and stage, histologic grade, depth of myometrial invasion and lymph node metastasis in endometrial carcinoma and to assess if vascular/lymphatic spaces invasion is predictable by Doppler ultrasound. Fifty-three patients with endometrial carcinoma were enrolled before surgical treatment. Transvaginal Color Doppler Ultrasound was performed to detect the areas of increased vascularity (>/=3) and to record the lowest resistance index (RI) from the blood flow signals within the tumour. Formalin fixed, paraffin embedded pathology slides were reviewed by a senior pathologist to evaluate histologic grading, depth of myometrial invasion, presence of lymph node metastasis and vascular/lymphatic spaces invasion. The number of patients with positive lymph node metastasis was too small to perform any statistical evaluation. Significantly lower RI was noted in tumours of advanced stage (>FIGO Stage I), tumours with higher histologic grade (Grade 3) and with presence of vascular invasion. No correlation was found for myometrial invasion (>50%). A high number of vascular areas was positively correlated with all the prognostic signs. Assessment of tumour changes in vascularity using colour Doppler ultrasound provides useful information for the preoperative prediction regarding stage and histologic grade. The good correlation between Doppler ultrasound results and histological finding of vascular/lymphatic spaces invasion is another point in favour of routine colour Doppler studies in patients with endometrial carcinoma. We believe this technique is useful both for preoperative staging and that recording of tumour recurrence pattern may lead to early selection of those patients that need additional therapy.

Clinical and endocrinological effects of 6 months of metformin treatment in young hyperinsulinemic patients affected by polycystic ovary syndrome.

Most patients with polycystic ovary syndrome (PCOS) have hyperinsulinemia; thus it has been postulated that insulin-lowering drugs, such as metformin, might be a useful long-term choice. We evaluated the effects of 6 months' administration of metformin on clinical and endocrine indices in PCOS patients. Forty-two hyperinsulinemic women with PCOS were continuously treated with metformin for 6 months. Gonadotropins, androgens (testosterone and androstenedione), insulin, sex hormone binding globulin (SHBG), lipid profile and clinical indices (menstrual length, body mass index (BMI), Ferriman-Gallwey score and waist/hip ratio (WHR)) were studied before and after metformin treatment. All women experienced a normalization of menstrual cycle length (reduction rate, 36.9%), a significant decrease in luteinizing hormone, insulin and androgen levels and an increase in SHBG plasma concentrations, with a concomitant decrease in cycle length and WHR. Significant changes were observed in the lipid profile. According to baseline androgen levels, patients were divided into two groups: 20 normoandrogenic and 17 hyperandrogenic women. The greatest decline of androgens, BMI and Ferriman-Gallwey score was observed in hyperandrogenic patients. Lowering of androgenicity was independent of BMI. Significant changes in lipid profile were observed in both groups after metformin treatment. These results suggest that metformin is effective in decreasing hyperandrogenism, mainly by reducing insulin levels. This leads to an improvement of clinical manifestations of PCOS and, in particular, of hyperandrogenism.

Modulation of endometrial redox balance during the menstrual cycle: relation with sex hormones.

This study aimed to evaluate the effects of changes in sex hormones occurring during the menstrual cycle on the redox balance and lipid peroxidation in normal human endometrial cells. Forty women, ages 21-41 yr, who were admitted to the Department of Gynecology and Obstetrics of the University of Bari for routine checkups or were treated for benign uterine disease, underwent endometrial biopsy and venipuncture. On the basis of histological examination, patients were allocated as follows: 10 in the early proliferative phase, 12 in the late proliferative phase, 8 in the early secretory phase, and 10 in the late secretory phase. LH, FSH (immunoradiometric essay), estradiol (E2), and progesterone (P(4)) (RIA) were determined in plasma samples. On the endometrial specimens, total glutathione (GSH), oxidized GSH (GSSG), malondialdehyde, and GSH peroxidase activity (GSH-Px) were determined. Significant cycle-dependent changes in endometrial GSH-Px (P < 0.0001), GSH (P < 0.001), and GSSG as a percentage of GSH (P < 0.0001) were observed. Malondialdehyde did not show significant differences. A linear regression model correlating sex hormone changes with redox indexes was performed. A significant positive correlation was observed between E2 and GSH-Px (r = 0.74; P = 0.0001), E2 and GSSG, as percentage of total (r = 0.84; P < 0.0001); a negative correlation was found between E2 and GSH (r = -0.57; P = 0.0001). No significant correlation was found between P(4) or FSH and oxidative balance. LH was found to be correlated with GSH-Px (r = 0.66; P = 0.0001) and GSSG as percentage of GSH (r = 0.5; P < 0.001). We conclude that the hormonal pattern is involved in maintaining the optimal redox balance in endometrium, mainly through modulation of GSH level and metabolism.

Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 agree with progression of ovarian endometriomas.

BACKGROUND: Changes in angiogenesis and expression of extracellular matrix-degrading enzymes have been substantiated in tumour changeover and progression. METHODS: Tissues from 44 biopsies of stage III and IV ovarian endometriomas, and 10 biopsies of normal (control) endometrium were investigated immunohistochemically to count microvessels, and by in situ hybridization to assess the expression of mRNA of matrix metalloproteinase-2 (MMP-2) and MMP-9. Implants of the tissues were investigated in the chick embryo chorioallantoic membrane (CAM) assay to determine their angiogenic capacity. RESULTS: The endometriomas displayed significantly higher counts than normal endometria and the highest values were associated with the deepest invasion level (stage IV). Microvessels localized in close association with ectopic endometrial cells in the form of winding and arborized tubes, often dilated in microaneurysmatic segments. These were absent in normal endometrium. Expression of MMP-2 and MMP-9 mRNA, evaluated as percentages of positive biopsies and intensity of expression, was up-regulated in endometriomas and more pronounced in stage IV. MMP-2 and MMP-9 mRNA were also expressed by host stromal cells, including microvascular endothelial cells, fibroblasts and macrophages, whereas the control endometrium showed very little expression of MMP-2 mRNA in a few endothelial cells and no expression of MMP-9 mRNA. Implants from stage IV endometrioma induced a more intense vasoproliferative response than those from stage III, while no vasoproliferative response was induced by the normal endometrium. CONCLUSION: These data suggest that angiogenesis and degradation of extracellular matrix occur together in endometriosis and are more pronounced in stage IV, and that endometriosis cells and some host stromal cell populations co-operate in disease progression.