Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression.

Regulatory T cells (Tregs) are thought to play a major role in pregnancy by inhibiting the maternal immune system and preventing fetal rejection. In decidual tissues, NK cells (dNK) reside in close contact with particular myelomonocytic CD14(+) (dCD14(+)) cells. Here we show that the interaction between dNK and dCD14(+) cells results in induction of Tregs. The interaction is mediated by soluble factors as shown by transwell experiments, and the prominent role of IFN-gamma is revealed by the effect of a neutralizing monoclonal antibody. Following interaction with dNK cells, dCD14(+) cells express indoleamine 2,3-dioxygenase (IDO), which, in turn, induces Tregs. Notably, unlike peripheral blood NK (pNK) cells, dNK cells are resistant to inhibition by the IDO metabolite L-kynurenine. "Conditioned" dCD14(+) cells also may induce Tregs through transforming growth factor-beta (TGF-beta) production or CTLA-4-mediated interactions, as indicated by the effect of specific neutralizing Abs. Remarkably, only the interaction between dNK and dCD14(+) cells results in Treg induction, whereas other coculture combinations involving either NK or CD14(+) cells isolated from peripheral blood are ineffective. Our study provides interesting clues to understanding how the crosstalk between decidual NK and CD14(+) cells may initiate a process that leads to Treg induction and immunosuppression. Along this line, it is conceivable that an impaired function of these cells may result in pregnancy failure.

Evaluation of patients' satisfaction of cervical ripening using dinoprostone by either intravaginal gel or pessary: an open-label, randomized, prospective study.

OBJECTIVE: To evaluate patient satisfaction of cervical ripening using dinoprostone (PGE2) by either intravaginal gel or pessary. STUDY DESIGN: A group of 173 nulliparous women requiring cervical ripening were recruited in the study and randomized to receive either intravaginal gel (Prepidil, Upjohn, Milan, Italy [group A]) or intravaginal pessary (Propess, Ferring Pharmaceuticals, Malmö, Sweden [group B]). Before administration of PGE2 and after delivery, the patients answered a questionnaire investigating the anxiety and discomfort caused by cervical ripening. RESULTS: Of the group, 22 women did not adequately complete the questionnaire; therefore 151 women were included in the study. Before cervical ripening, anxiety and discomfort did not significantly differ between the two study groups; more patients in group A than in group B declared they would have preferred the other form of application. The intensity of pain experienced during the application of PGE2 was higher in group B than in group A. For the future opportunity to choose the application necessary for cervical ripening, more patients in group B than in group A would change the form of application. CONCLUSION: Patient satisfaction with the two forms of treatment appears to be equally good. The application of the intravaginal pessary causes more discomfort than the vaginal gel.

Frozen section underestimates the need for surgical staging in endometrial cancer patients.

OBJECTIVE: To compare the risk status for lymph nodal metastasis at frozen section in endometrial cancer by applying a model based on tumor grade and myometrial involvement. STUDY DESIGN: A retrospective analysis was performed on 174 early-stage endometrial cancer patients on whom an intraoperative frozen section was requested. Patients were retrospectively divided into low, intermediate, and high risk for lymph nodal involvement based on tumor grade and myometrial invasion based on Gynecologic Oncology Group 33 data. Concordance of risk status at frozen and permanent sections was performed. RESULTS: Risk status at frozen and permanent sections were highly correlated (P < 0.01). Agreement between frozen and permanent sections was substantial (kappa = 0.625). In 16% of the cases, frozen section underestimated the risk when compared with permanent section. CONCLUSION: Relying on intraoperative frozen section of the uterus to assess risk status for lymph nodal involvement in early-stage endometrial cancer patients leads to suboptimal management in a substantial number of cases.

Uterine adenomyosis in persistence of dysmenorrhea after surgical excision of pelvic endometriosis and colorectal resection.

OBJECTIVE: To determine whether the presence of uterine adenomyosis may impair the amelioration of pain symptoms after laparoscopic excision of pelvic endometriosis combined with colorectal resection. STUDY DESIGN: This prospective study included 50 women with bowel endometriosis with or without uterine adenomyosis. Presence of uterine adenomyosis was investigated by magnetic resonance imaging. Patients underwent excision of pelvic endometriosis and colorectal resection; some patients with focal adenomyosis underwent uterine surgery. Pain symptoms and gastrointestinal complaints were evaluated before surgery and at 6, 12 and 18 months' follow-up. RESULTS: At 6-month follow-up, dysmenorrhea significantly improved in women without uterine adenomyosis and in those with adenomyosis that was excised at surgery; this improvement persisted at 18 months' followup. No significant improvement in dysmenorrhea was observed in women with adenomyosis not excised at surgery. Deep dyspareunia and chronic pelvic pain significantly improved at follow-up in all study groups. Most of gastrointestinal symptoms improved or disappeared at 6 months' follow-up; the improvement in gastrointestinal function persisted at 18 months' follow-up. CONCLUSION: Excision of pelvic endometriosis combined with bowel resection significantly improves chronic pelvic pain, dyspareunia and gastrointestinal symptoms; however, the presence of uterine adenomyosis may determine persistence of dysmenorrhea.

GnRH analogue remarkably down-regulates inflammatory proteins in peritoneal fluid proteome of women with endometriosis.

OBJECTIVE: To determine the changes in the peritoneal fluid proteome of women with endometriosis determined by the administration of gonadotropin-releasing hormone analogues (GnRH-a). STUDY DESIGN: Peritoneal fluid samples were collected during laparoscopy from patients under GnRH-a and from women who did not receive any type of hormonal treatment in the 6 months before surgery. Samples were subjected to 2-D gel electrophoresis and compared by computerized analysis. Protein spots differentially expressed between the study groups were identified by liquid chromatography tandem mass spectrometry. RESULTS: More than 470 protein spots were analyzed. Several proteins with significant alterations were found. The down-regulated molecules were isoforms of alpha 2-HS glycoprotein, alpha 1-antitrypsin, S100-A8, haptoglobin alpha chain and vitamin D-binding protein. No protein spot had significantly higher expression in peritoneal fluid of women under GnRH-a than in untreated patients. CONCLUSION: Several inflammatory molecules present in peritoneal fluid are down-regulated during treatment with GnRH-a; administration of this drug reduces the inflammation in the peritoneal cavity.

Proteomic analysis of peritoneal fluid in fertile and infertile women with endometriosis.

OBJECTIVE: To evaluate the peritoneal fluid (PF) proteome of fertile and infertile women with endometriosis. STUDY DESIGN: PF samples were collected at laparoscopy from 26 fertile women and 26 infertile ones. Samples were subjected to 2-dimensional gel electrophoresis and compared by computerized analysis. Protein spots were identified by liquid chromatography tandem mass spectrometry. RESULTS: One isoform of immunoglobulin light chain spot was more frequently present in PF of infertile women than infertile patients. Nine protein spots had significantly higher expression in PF of infertile patients than infertile controls. They were 2 isoforms of serotransferrin, 1 isoform of complement C3, serum amyloid P-component, alpha-1-antitrypsin and clusterin; 3 protein spots remain unidentified. No protein spots had significantly lower expression in PF of infertile women with endometriosis than in PF of fertile controls. Complement C3 had higher PF levels in the luteal than in the follicular phase of the menstrual cycle in both infertile and fertile patients. CONCLUSION: Among women with endometriosis, those with infertility have aberrant expression of several PF proteins; most of these molecules are involved in the immune response.

Increased expression of one isoform of leucine-rich alpha-2-glycoprotein in peritoneal fluid of women with uterine leiomyomas.

OBJECTIVE: To compare the peritoneal fluid (PF) proteome of women with and without uterine leiomyomas. STUDY DESIGN: PF samples were collected at laparoscopy from 14 women with uterine leiomyomas and 14 patients without leiomyomas who underwent tubal sterilization. PF samples were subjected to two-dimensional gel electrophoresis, silver stained, digitally captured, and compared by computerised analysis. Protein spots with aberrant expression in PF of women with leiomyomas were identified by liquid chromatography tandem mass spectrometry. RESULTS: One isoform of leucine-rich alpha-2-glycoprotein (LRGm), one immunoglobulin light chain, and one unidentified protein (pI: 5.62; M(r): 51.1 kDa) had significantly higher expression in PF of women with leiomyomas. Two isoforms of fibrinogen gamma chain had decreased expression in PF of women with uterine leiomyomas. Following Bonferroni correction for multiple comparisons, the aberrant expressions of LRGm and of one isoform of fibrinogen gamma chain was confirmed. The expression of these molecules was not affected by the phase of the menstrual cycle. CONCLUSIONS: Uterine leiomyomas are associated with changes in proteins present within the peritoneal fluid. The physiopathological relevance of the increased expression of LRGm in PF of women with uterine leiomyomas remains unclear.

Proteomics technologies in endometriosis.

Endometriosis is a common disorder that is associated with infertility and pelvic pain. Diagnosis is based on the visualization of endometriotic lesions during surgery as no reliable serum marker is currently available. The etiology of endometriosis is largely unknown. Over the last 20 years, several proteomics technologies have been used to research novel proteins with a potential etiological role in endometriosis, and to identify candidate serum markers for this condition. While some molecules identified by proteomics technologies may have a relevant role in the pathogenesis of endometriosis, the research of potential serum markers for this condition is still far from any clinical application. This review summarizes the state of the art and potential applications of proteomics in endometriosis research.

Peritoneal fluid proteome in women with different ASRM stages of endometriosis.

OBJECTIVE: Endometriosis has a wide range of severity but molecular factors associated with variable extension of the disease have not been widely investigated. The present study compares the peritoneal fluid (PF) proteome of 109 women with endometriosis and different disease stage as defined by the American Society for Reproductive Medicine (ASRM). METHODS: PF samples were subjected to two-dimensional gel electrophoresis; protein spots of interest were identified by liquid chromatography tandem mass spectrometry. RESULTS: Over 470 protein spots were analyzed. One isoform of haptoglobin alpha chain, alpha-1b-glycoprotein and one unknown protein had higher expression in PF of women with ASRM stage I-II endometriosis. Four isoforms of alpha1-antitrypsin, three isoforms of alpha-1b-glycoprotein, one isoform of S100-A8 and serotransferrin had higher expression in PF of women with ASRM stage III-IV disease. CONCLUSIONS: Several protein isoforms have different expression in PF of women with ASRM stage I-II endometriosis than in those with ASRM stage III-IV disease; most of these molecules are involved in inflammation and immune response.

A prospective, randomised, controlled clinical study on the assessment of tolerability and of clinical efficacy of Merional (hMG-IBSA) administered subcutaneously versus Merional administered intramuscularly in women undergoing multifollicular ovarian stimulation in an ART programme (IVF).

BACKGROUND: Multifollicular ovarian stimulation (MOS) is widely used in IVF and the compliance to treatment is deeply influenced by the tolerability of the medication(s) used and by the ease of self-administration. This prospective, controlled, randomised, parallel group open label, multicenter, phase III, equivalence study has been aimed to compare the clinical effectiveness (in terms of oocytes obtained) and tolerability of subcutaneous (s.c.) self-administered versus classical intramuscular (i.m.) injections of Merional, a new highly-purified hMG preparation. METHODS: A total of 168 normogonadotropic women undergoing IVF were enrolled. Among them, 160 achieved pituitary suppression with a GnRH-agonist long protocol and were randomised to MOS treatment with Merional s.c. or i.m. They started MOS with a standard hMG dose between 150-300 IU, depending upon patient's age, and underwent a standard IVF procedure. RESULTS: No statistically significant difference in the mean number of collected oocytes (primary endpoint) was observed between the two study subgroups (7.46, SD 4.24 vs. 7.86, SD 4.28 in the s.c. and i.m. subgroups, respectively). As concerns the secondary outcomes, both the pregnancy and the clinical pregnancy rates were comparable between subgroups. The incidence of adverse events was similar in the two groups (2.4% vs. 3.7%, respectively). Pain at injection site was reported only the i.m. group (13.9% of patients). CONCLUSION: Merional may be used by s.c. injections in IVF with an effectiveness in terms of retrieved oocytes that is equivalent to the one obtained with i.m administration and with a better local tolerability. With the limitations due to the sample size af this study, s.c. and i.m. administration routes seem to have the same overall safety.

Bowel endometriosis: presentation, diagnosis, and treatment.

UNLABELLED: Bowel endometriosis opens a new frontier for the gynecologist, as it forces the understanding of a new anatomy, a new physiology, and a new pathology. Although some women with bowel endometriosis may be asymptomatic, the majority of them develop a variety of gastrointestinal complains. No clear guideline exists for the evaluation of patients with suspected bowel endometriosis. Given the fact that, besides rectal nodules, bowel endometriosis can not be diagnosed by physical examination, imaging techniques should be used. Several techniques have been proposed for the diagnosis of bowel endometriosis including double-contrast barium enema, transvaginal ultrasonography, rectal endoscopic ultrasonography, magnetic resonance imaging, and multislice computed tomography enteroclysis. Medical management of bowel endometriosis is currently speculative; expectant management should be carefully balanced with the severity of symptoms and the feasibility of prolonged follow-up. Several studies demonstrated an improvement in quality of life after extensive surgical excision of the disease. Bowel endometriotic nodules can be removed by various techniques: mucosal skinning, nodulectomy, full thickness disc resection, and segmental resection. Although the indications for colorectal resection are controversial, recent data suggest that aggressive surgery improves symptoms and quality of life. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to describe the varied appearance of bowel endometriosis, recall that it is difficult to diagnose preoperatively, and explain that surgical treatment offers the best treatment in symptomatic patients through a variety of surgical techniques which is best accomplished with a team approach.

Atherosclerosis in women with endometriosis.

OBJECTIVE: This study aims to determine whether women with endometriosis have greater subclinical atherosclerosis than the general population. STUDY DESIGN: This case-control study included 66 women with endometriosis and 66 controls matched for age and body mass index. All subjects were >or=35 years old. Exclusion criteria were obesity, diabetes, hypertension, hyperlipidemia, renal or metabolic diseases. Before laparoscopy, all patients underwent a measurement of intima-media thickness (IMT) and distensibility coefficient (DC) on the common carotid artery. In addition, blood samples were taken to determine the levels of lipids, fibrinogen, C-reactive protein, homocysteine, fasting glycemia, antithrombin III, plasminogen, protein C, protein S, and activated protein C resistance. RESULTS: All the biochemical parameters evaluated had similar levels in the two study groups. IMT was similar in women with endometriosis and in controls both on left (p=0.330) and right (p=0.648) carotid artery. Similarly, no significant difference was observed in the DC between women with endometriosis and controls both on left (p=0.539) and right (p=0.178) carotid artery. No significant difference was observed in IMT and DC between women with mild and severe endometriosis. CONCLUSION: Women with endometriosis do not have more subclinical atherosclerosis than the general population.

What is the desired menstrual frequency of women without menstruation-related symptoms?

INTRODUCTION: This study aimed to investigate the desired menstrual frequency of subjects without menstruation-related symptoms. MATERIALS AND METHODS: The study included 270 women of reproductive age. Women with menstrual headache, dysmenorrhea, hypermenorrhea and/or premenstrual syndrome were excluded. The study subjects completed a standardized questionnaire. RESULTS: Of the women, 75.6% declared that menstrual periods interfere with their sexual life, 28.8% preferred not having their menstrual period when at work and 48.4% reported that menstrual periods interfere with practicing sports. Given the choice, 28.5% of the women would desire amenorrhea and 27.8% would prefer a reduction in the frequency of menstrual periods. Of the 152 women desiring to reduce menstrual frequency, 73.0% declared that they would accept to use a drug to reduce menstrual frequency. CONCLUSIONS: Over 50% of women without menstruation-related symptoms would like to lessen the frequency of menstrual periods and about 50% of them would desire amenorrhea.

Transvaginal sonohysterographic evaluation of uterine malformations.

OBJECTIVE: The aim of this study was to assess the diagnostic value and the usefulness of sonohysterography (SHG) in the detection of uterine anomalies, compared with other diagnostic methods. STUDY DESIGN: From January 2002 to December 2003, we collected 54 patients with a history of primary or secondary infertility or repeated spontaneous abortion and with a clinically or sonographically suspected abnormal uterus. All patients had previously undergone hysterosalpingography (ISG). All patients were examined by standard transvaginal ultrasound. Sonohysterography was then carried out by the intrauterine injection of an isotonic saline solution. Suspected uterine anomalies were also confirmed by hysteroscopy (HS) and/or laparoscopy. RESULTS: Sonohysterography was able to detect all the anomalies. The sensitivity and specificity of sonohysterography were the same as for hysteroscopy. However, there was no significant difference between the diagnostic capabilities of the methods analyzed. CONCLUSIONS: Transvaginal sonohysterography with saline solution is a low-cost, easy, and helpful examination method for uterine malformations. We propose that sonohysterography should be performed for the primary investigation of infertility and repeated miscarriages.

Quality of sex life in women with endometriosis and deep dyspareunia.

OBJECTIVE: To characterize sexual function among women with endometriosis and deep dyspareunia (DD). DESIGN: Cross-sectional survey. SETTING: University teaching hospital. PATIENT(S): Three-hundred nine women undergoing surgery because of infertility, pelvic pain, or adnexal masses. Three groups of patients with DD were created: women with deep infiltrating endometriosis of the uterosacral ligament (group U), women with endometriosis without uterosacral ligament lesions (group E), and controls (group C). INTERVENTION(S): Laparoscopy. MAIN OUTCOME MEASURE(S): Sexual function questionnaire. RESULT(S): The prevalence of DD since the first intercourse was significantly higher among women with endometriosis than in controls (P=.029). When group U was compared with group E and C, the pain score was higher, the number of intercourses per week was reduced, the orgasm was less satisfying, and the patients felt less relaxed and fulfilled after sex. No significant difference was observed in pain score and coital frequency between subjects with monolateral and bilateral lesions of the uterosacral ligament. CONCLUSION(S): Among subjects with DD, those with deep infiltrating endometriosis of the uterosacral ligament have the most severe impairment of sexual function; the presence of bilateral lesions does not influence the severity of the symptoms. Women with endometriosis have frequently suffered DD during their entire sex lives.

Future perspectives in the medical treatment of endometriosis.

UNLABELLED: In the last few years, our understanding of the pathogenesis of endometriosis at the cellular and molecular levels has improved significantly. This may give us the opportunity to use new, specific agents for the treatment of this disorder. Despite the effectiveness of the available treatments, novel therapeutic strategies may improve our ability to eliminate endometriotic lesions when present and to prevent the recurrence of endometriosis after surgical treatment. This review focuses on the new, experimental approaches to the medical treatment of endometriosis and its symptoms. The blockage of aromatase activity in endometriotic lesions with an aromatase inhibitor may represent a new step in the medical treatment of endometriosis. Preliminary clinical studies have demonstrated the efficacy of third-generation nonsteroidal aromatase inhibitors (ie, anastrozole and letrozole) in reducing the intensity of pain symptoms associated with the presence of endometriosis. The new selective progesterone receptor modulators may represent a valid hormonal treatment option. Therapeutic manipulation of the immune system through TNFalpha inhibitors may be beneficial in women with endometriosis. New pharmaceutical agents affecting inflammation, angiogenesis, and matrix metalloproteinase activity may prevent or inhibit the development of endometriosis. Further clinical trials may determine if these new therapies are superior to current medical treatment strategies for endometriosis. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians Learning. OBJECTIVES: After completion of this article, the reader should be able to describe the new experimental medical treatments of endometriosis, state that the clinical use of nonsteroidal aromatase inhibitors for endometriosis appears to be efficacious but is based on preliminary clinical data, and recall that the drugs used for endometriosis in the future may include manipulation of the immune system.

Body mass index in endometriosis.

OBJECTIVE: Previous studies did not establish a clear correlation between the presence of endometriosis and the values of body mass index (BMI). STUDY DESIGN: The BMI of 366 women with endometriosis was compared to that of 248 controls undergoing laparoscopy because of benign gynaecological conditions. Significant differences at univariate analyses were confirmed by using Analysis of covariance (ANCOVA) to control for potential confounding variables. RESULTS: BMI was significantly lower in women with endometriosis than in controls (p < 0.001); this difference was confirmed when the analysis was restricted to subjects with normal BMI (18.50-24.99 kg/m(2)) (p = 0.002). 4.8% of control subjects and no woman with endometriosis were obese. No significant difference was observed in the BMI of women with mild (revised classification of the American Fertility Society, rAFS I-II) and severe endometriosis (rAFS III-IV). CONCLUSION: Women with endometriosis have lower BMI and are less frequently obese than control subjects. Further studies should investigate the physiopathological basis of decreased BMI in women with endometriosis.

Myasthenia gravis: management issues during pregnancy.

Myasthenia gravis (MG) often affects women in the second and third decades of life, overlapping with the childbearing years. The course of the disease is unpredictable during pregnancy; however, worsening of symptoms occurs more likely during the first trimester and postpartum. MG can be well managed during pregnancy with relatively safe and effective therapies. Anticholinesterase drugs are the mainstay of treatment, when MG symptoms are not satisfactorily controlled, corticosteroids, azathioprine and in some cases cyclosporin A can be used. Until information is available regarding safety, mycophenolate mofetil should be discontinued before pregnancy. Pregnancy should be avoided in women treated with methotrexate because of the risk of causing typical malformations. Plasmapheresis and intravenous immunoglobulins have been successfully used in the treatment of MG crisis during pregnancy. Caesarean section is recommended only for obstetric reasons; forceps delivery and vacuum extraction are sometimes required. Epidural anesthesia is advised to reduce physical and emotional stress. MG during pregnancy can lead to serious life-threatening conditions, including respiratory insufficiency; therefore, intensive checkups by a gynaecologist and a neurologist are necessary. Women with myasthenia gravis should not be discouraged from conceiving; however, they should discuss their plan for pregnancy with their neurologist and their gynaecologist.

The association between p53 expression, stage and histological features in endometrial cancer.

OBJECTIVE: Alterations of the p53 gene have been widely suggested to be relevant to the development of endometrial carcinoma. However, contradictory results have been reported when immunohistochemical determination of p53 expression has been correlated with stage and histological features of the tumours. STUDY DESIGN: Pathology findings were reviewed and p53 immunoperoxidase staining was performed in 240 cases of endometrial carcinoma. RESULTS: Uterine papillary serous adenocarcinomas showed significantly higher p53 overexpression than uterine endometrioid adenocarcinomas (100.0% versus 61.0%, p<0.005). p53 overexpression was significantly higher in the secretory variant (85.7%) than in the typical endometrioid carcinoma (60.0%) (p<0.05). p53 expression did not differ between early (stage I) and advanced (stage II-IV) carcinomas. Likewise, no difference was observed in p53 expression among different architectural grades. The incidence of metastasis to lymph nodes was similar in p53 positive (13.7%) and in p53 negative tumours (12.5%). CONCLUSION: In the present series, p53 immunostaining did not differ between cases with different FIGO stages or histologic characteristics of the tumours. No simple relationship exists between the immunohistochemical determination of p53 expression and the biological aggressiveness of endometrial carcinomas.

Pregnancy despite IUD: adverse effects on pregnancy evolution and fetus.

INTRODUCTION: In this retrospective study, we describe cases of pregnancy initiated despite an intrauterine device (IUD), which occurred in our setting in the last 10 years (from January 1992 to December 2001), aiming to point out the effects of IUD in terms of miscarriage or fetal problems. METHODS: Histopathologic reports of IUD pregnancies at any gestational age were found by computer search and analyzed. The characteristics of embryo-fetuses and of decidua-placenta were recorded and compared. RESULTS: Ten IUD pregnancies were found: 3 ended with first-trimester voluntary termination of pregnancy, 2 with second-trimester elective abortions, 2 were miscarried during first trimester (spontaneous abortions) and 3 were carried to term. No relevant abnormalities were found in the development of the embryo-fetuses, except for one case of a newborn with upper lip lesion and a mild deviation of nasal septum. Alterations of the placenta and adnexa were found only in the two miscarriage cases. CONCLUSIONS: The small number of cases found reflects the very low incidence of pregnancies initiated despite an IUD, although an increasing trend has been recorded in the last 5 years, probably concurrently with an increasing immigration flow into our area. Our findings suggest that if the embryo, despite the IUD, can reach a firm attachment during the first weeks of gestation, the pregnancy usually continues to term. It is notable that in this case series a major lip defect occurred in 1 of 10 described cases (10%), suggesting that although pregnancies with IUD are exceptional, fetal abnormalities seem not.