Androgen receptor gene cytosine, adenine, and guanine trinucleotide repeats in patients with endometriosis.

OBJECTIVE: A genetic variation in the androgen receptor (AR) has been associated with the risk of developing endometriosis. The AR gene is located on the X chromosome and contains a highly polymorphic trinucleotide repeat (cytosine, adenine, and guanine: CAG) in its first exon, whose length and methylation pattern affect both AR expression and function. Thus, we sought to further investigate the potential association between endometriosis and the AR-CAG polymorphism. METHODS: Genomic DNA was obtained from a consecutive series of 197 white Italian women of reproductive age who underwent laparoscopy for benign gynecologic pathologies. Molecular analysis of AR-CAG repeats was performed by polymerase chain reaction amplification and Genescan evaluation. The pattern of CAG repeat distribution was compared between subjects with and without endometriosis. RESULTS: Endometriosis was documented in 105 women (stage I-II in 33 women and stage III-IV in 72 women). We found no difference in the number of AR-CAG repeats between women with endometriosis and controls. The CAG repeat length ranged from eight to 27 (mean +/- standard deviation, 17.4 +/- 1.9) for endometriosis patients and from 11 to 27 (mean +/- standard deviation, 17.4 +/- 2) for controls. Moreover, no association was found between AR gene polymorphisms and the various clinical manifestations of the disease. CONCLUSION: We conclude that AR-CAG repeat length does not constitute an important factor for the genetic predisposition to endometriosis.

Association rate between deep peritoneal endometriosis and other forms of the disease: pathogenetic implications.

BACKGROUND: It has been suggested recently that deep endometriosis and the other forms of the disease do not share a common pathogenetic mechanism. In this study, we hypothesize that, if this is true, deep peritoneal endometriosis and the other forms should not be significantly associated. METHODS: Clinical and surgical records of all women who were referred to the Department of Obstetrics and Gynecology, Clinica 'L.Mangiagalli' between January 1995 and June 2002 and who were diagnosed with deep peritoneal pelvic endometriosis at the time of surgery were retrieved. The concomitant presence of superficial endometriotic implants, endometriomas and pelvic adhesions was evaluated. A binomial probability distribution model was used to calculate the 95% confidence interval (95% CI) of the association rates. RESULTS: Ninety-three women with deep peritoneal endometriosis were identified. The presence of superficial endometriotic implants, endometriomas and pelvic adhesions was documented in 61.3% (95% CI 51.4-71.2%), 50.5% (95% CI 40.3-60.7%) and 74.2% (95% CI 65.3-83.1%) of patients with deep endometriotic nodules, respectively. Overall, deep peritoneal endometriosis was the only form of the disease in only 6.5% (95% CI 2.8-12.3%) of cases. No relevant differences regarding these associations were observed according to the location and the size of the deep endometriotic nodules. CONCLUSIONS: Results from this study do not support the hypothesis that deep endometriosis should be considered as a distinct entity of the disease.

Expression of interleukin-10 and its receptor is up-regulated in early pregnant versus cycling human endometrium.

Previous reports suggest that systemic and/or placental presence of T helper 2-type cytokines would be supportive of normal pregnancy. Among these cytokines, IL-10 is thought to be produced at the feto-maternal interface to control fetal-ablating immune responses. However, expression of IL-10 in nonhemopoietic maternal cells of the human uterus has not been characterized in detail. Thus, we studied the expression and modulation of the cytokine and its receptor in human endometrial cells obtained in different phases of the cycle and in early pregnancy. Both cycling and pregnant endometrium express the genes for IL-10 and its receptor, but secretion of the cytokine was significantly increased in decidual cultures compared with that by endometrial cells in both proliferative and secretory phases of the cycle. Similarly, the expression of IL-10 receptor mRNA was up-regulated in early decidua compared with that in menstrual cycle-dependent endometrium. IL-1beta, but not gonadal steroid hormones, was able to directly increase endometrial/decidual IL-10 production. Based on the activity of IL-10 in other nonhemopoietic cell populations, we also evaluated its potential effects on TNFalpha secretion and proliferation of endometrial/decidual cells, but we were unable to demonstrate any direct role of IL-10 as a regulator of these specific functions. It is evident that IL-10 and its receptor are normal constituents of endometrium and early decidua, and their up-regulation during early pregnancy may participate in the T helper type 2 predominance at the feto-maternal interface. The inability of the cytokine to exert autocrine effects on TNFalpha secretion and proliferation of decidual cells leads to speculation that the cytokine acts mostly as a paracrine mediator able to affect maternal immune responses.

Endometriosis: novel etiopathogenetic concepts and clinical perspectives.

OBJECTIVE: To discuss current ideas about therapy for endometriosis derived from new observations generated by using molecular biology techniques and in vivo animal models of disease. METHOD(S): The MEDLINE database was reviewed for English-language articles on new drugs that affect the endocrine or immunologic system, the possibility that endometriosis has multiple forms, and the association of endometriosis with cancer. Specific attention was given to in vivo studies in animals or humans. CONCLUSION(S): Among the novel potential candidate drugs, aromatase inhibitors and raloxifene should be considered for treatment of postmenopausal women with endometriosis. Notable observations have emerged from studies of immunomodulators and antiinflammatory agents in animal models of disease. These findings must be confirmed in women. The histogenesis of ovarian endometriomas is still unclear, thus limiting new experimental approaches to this form of disease. Given the low but established risk for malignant transformation of endometriosis, efforts should be directed toward identification of susceptibility loci for the disease and its potential transformation into cancer.

Risk factors for spontaneous preterm birth: a Northern Italian multicenter case-control study.

Preterm birth remains one of the most serious problems facing obstetricians. The aim of this study was to investigate the risk factors for spontaneous preterm birth in northern Italy. Nine different collaborating institutions participated in this multicenter case-control study. Cases were defined as women who were spontaneously delivered of a live singleton newborn between 20 and 37 weeks of gestation. One control was matched to each case by delivery date, maternal age and parity. Seven hundred and fifty-four cases and 754 controls were available for data analysis. Demographic and clinical characteristics were obtained using a standardized questionnaire. At the time of hospital admission, urine and cervico-vaginal samples were collected and tested for bacterial infections and bacterial vaginosis, respectively. Variables found to be statistically significant in the univariate analysis were entered in a multivariate model to examine their independent effects. In order of decreasing odds ratios (ORs), the factors that showed a significant association with preterm delivery were: previous preterm birth (OR 5.7, confidence interval (CI) 2.5-12.9); second-trimester miscarriages (OR 4.4, CI 1.3-15.3); genital bleeding before 24 weeks of gestation (OR 2.5, CI 1.6-3.8); bacterial vaginosis (OR 2.0, CI 1.3-3.1), and previous genital infections (OR 1.6, CI 1.1-2.5). This study confirms that infections play a role in the etiology of preterm birth and that reproductive history is still the most important factor in identifying women at increased risk.

Use of serum-soluble intercellular adhesion molecule-1 as a new marker of endometriosis.

OBJECTIVE: To investigate the hypothesis that soluble intercellular adhesions molecule-1 (sICAM-1) may be used as a new serum marker of endometriosis. DESIGN: Prospective cohort study. SETTING: An academic department specializing in gynecologic laparoscopy. PATIENT(S): Consecutive series of 120 women of reproductive age who underwent laparoscopy for benign gynecologic conditions. INTERVENTION(S): Data were collected on baseline clinical characteristics, and surgical and histologic diagnosis. MAIN OUTCOME MEASURE(S): Serum concentration of both CA125 and sICAM-1. RESULT(S): Endometriosis was documented in 71 women (stage I to II in 24 cases and stage III to IV in 47 cases). Serum levels of sICAM-1 were only slightly but not significantly increased in women with endometriosis compared with women without the disease. However, serum concentration of sICAM-1 in the 21 women who were found to have deep peritoneal endometriosis was significantly enhanced when compared with both women without the disease and those with other forms of endometriosis. The sensitivity and specificity of sICAM-1 in detecting deep peritoneal endometriosis were 0.19 and 0.97, respectively; whereas those of CA125 were 0.14 and 0.92, respectively. When both parameters were used concomitantly, the sensitivity and specificity were 0.28 and 0.92, respectively. CONCLUSION(S): Although the present study tends to support a role of sICAM-1 in the development of endometriosis, serum concentrations of this molecule do not seem to be an effective indicator for the diagnosis of either the early or advanced stage of endometriosis. However, an integrated clinical and laboratory approach using both CA125 and sICAM-1 may be helpful in specifically identifying women with deep peritoneal endometriosis.

Serum leptin concentrations in endometriosis.

It has been recently reported that serum concentrations of the adipocyte-derived hormone leptin are increased in patients affected by endometriosis. On the basis of these findings, the present study was undertaken to evaluate whether the protein may be used as a new serum marker of the disease. A consecutive series of 67 reproductive-age women who underwent laparoscopy for benign gynecological pathologies were enrolled prospectively for the study. Serum leptin concentrations, as evaluated by a conventional RIA kit, were related to baseline clinical characteristics and surgical and histologic diagnosis. Endometriosis was documented in 42 women (stage I-II in 19 patients and stage III-IV in 23 patients). Twenty-five women of similar age and body mass index, who had no laparoscopic evidence of the disease, served as control group. Serum levels of leptin resulted similar between women without and with endometriosis at any stage (mean +/- SEM, 12.5 +/- 9.4 ng/ml and 12.1 +/- 8.0 ng/ml, respectively). No significant association with leptin concentrations was observed in regard to stage of the disease, number of endometriotic implants, presence/absence of an endometriotic cyst or peritoneal deep endometriosis, and presence/absence of specific symptoms. Therefore, our results do not support the possibility to employ leptin measurement as a diagnostic tool for endometriosis. Further studies are needed to elucidate the relationship between leptin and endometrial system and determine the potential contribution of the molecule in implantation and early pregnancy development.

Human chorionic gonadotropin patterns after a single dose of methotrexate for ectopic pregnancy.

OBJECTIVE: The great variability in human chorionic gonadotropin (HCG) levels after a single dose of methotrexate (MTX) for ectopic pregnancy makes it difficult to predict treatment failure. We describe different patterns of HCG levels. STUDY DESIGN: Fifty patients were injected i.m. with 50mg/m(2) of MTX for an ectopic pregnancy. Venous blood samples for HCG detection were obtained on the day of treatment (day 0), day 3 and day 7 and weekly until values were undetectable. Patients were classified as: group 1, persistent pathology (n=11); group 2, complete resolution with a decrease of HCG levels at day 3 (n=30); group 3, complete resolution after a rise of HCG values at day 3 (n=9). Statistical analysis was performed using the Mann-Whitney non-parametric test with 95% confidence intervals. RESULTS: Values of day 0 were similar for all the groups. HCG levels of group 3 decreased rapidly after day 3 and at day 7 they were significantly different from levels of group 1. Differences in HCG levels between groups 2 and 3 became indistinguishable from day 21. CONCLUSION: The observation of patients undergoing resolution after an initial increase of HCG levels justify an expectant management for 1 week in clinically stable patients. The strategy to separate HCG curves in patients undergoing resolution may shed light on the different clinical responses to therapy for ectopic pregnancies. However, the phenomenon of the immediate rise of HCG should be better investigated.