Adenomyosis: What the Patient Needs.

A panel of experts in the field of endometriosis expressed their opinions on management options in a 28-year-old patient, attempting pregnancy for 1 year, with severe cyclic pelvic pain and with clinical examination and imaging techniques suggestive of adenomyosis. Many questions this paradigmatic patient may pose to the clinician are addressed, and all clinical scenarios are discussed. A decision algorithm derived from this discussion is also proposed.

Vaginal Uterine Morcellation Within a Specimen Containment System: A Study of Bag Integrity.

STUDY OBJECTIVE: To evaluate the integrity of the endoscopic bag after transvaginal in-bag morcellation of uteri that need to be removed by vaginal morcellation during total laparoscopic hysterectomy (TLH). DESIGN: Prospective pilot study (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: Twelve patients with uteri that needed to be removed and who required vaginal morcellation underwent TLH from September 2014 to February 2015, without suspected or confirmed malignancy. INTERVENTIONS: After transvaginal in-bag morcellation of uteri at the end of TLH, careful visual inspection of the endoscopic pouch, using diluted methylene blue, was carried out, highlighting any minimal bag damage. MEASUREMENTS AND MAIN RESULTS: No gross rupture was encountered after morcellation; however, 4 minimal ruptures were recognized (33%) after filling up the bag with diluted methylene blue. CONCLUSIONS: Minimal lesions of the bag may occur after transvaginal morcellation of uteri that need to be removed by vaginal morcellation; this may potentially affect the spread of cancer cells into the abdominal cavity.

How to Manage Bowel Endometriosis: The ETIC Approach.

A panel of experts in the field of endometriosis expressed their opinions on management options in a 35-year-old patient desiring pregnancy with a history of previous surgery for endometrioma and bowel obstruction symptoms. Many questions that this paradigmatic patient may pose to the clinician are addressed, and various clinical scenarios are discussed. A decision algorithm derived from this discussion is proposed as well.

Surgical excision of ovarian endometriomas: Does it truly impair ovarian reserve? Long term anti-Müllerian hormone (AMH) changes after surgery.

AIM: The long-term effects of laparoscopic cystectomy on ovarian reserve in patients with unilateral and bilateral ovarian endometriomas were evaluated. METHODS: A total of 22 patients undergoing laparoscopic cystectomy for unilateral endometrioma (n = 10) and bilateral endometriomas (n = 12) were included in the study. RESULT(S): Serum anti-Müllerian hormone (AMH) levels significantly decreased from the baseline value (3.98 ± 3.27 ng/mL) one (1.67 ± 1.56 ng/mL), three (2.01 ± 1.70 ng/mL), and six months (2.43 ± 2.39 ng/mL) postoperatively. There was no difference between preoperative and 12 month postoperative AMH levels (4.01 ± 3.39 ng/mL) (P > 0.05). Patients with bilateral endometriomas had a significantly higher rate of decline in AMH levels 12 months after surgery than patients with monolateral endometriomas (P = 0.035), but in both groups there was no difference in AMH levels at one and 12 months postoperatively (P > 0.05). CONCLUSION(S): AMH levels temporarily decreased after laparoscopic cystectomy for ovarian endometriomas, with complete recovery of preoperative AMH values at 12 months postoperatively. This pattern was equal in patients with bilateral and unilateral ovarian involvement. Patients with bilateral cysts have higher rates of decline of AMH levels compared to patients with unilateral affection.

An Italian association study and meta-analysis with previous GWAS confirm WNT4, CDKN2BAS and FN1 as the first identified susceptibility loci for endometriosis.

BACKGROUND: Although endometriosis may benefit from primary prevention measures, the epidemiological risk factors identified are equivocal. Two genome-wide association studies (GWAS) have been conducted for endometriosis in two different ethnic populations but results are still to be replicated consistently and across various ethnicities. To confirm the association of GWAS-derived susceptibility loci, we conducted a replication Italian case-control study and a meta-analysis. METHODS: An independent set of 305 laparoscopically-proven endometriosis patients and 2710 controls were recruited. Four SNPs-CDKN2BAS rs1333049, rs7521902 close to WNT4, rs12700667 in an inter-genic region on 7p15.2 and fibronectin 1 rs1250248-were selected for this association study. RESULTS: Rs1333049 risk allele G frequency resulted significantly higher in endometriosis patients compared with controls (OR 1.32, 95% CI 1.11 to 1.57), confirming the role of this locus also in the Caucasian population. The meta-analysis showed that rs7521902 was associated with endometriosis at a genome-wide significance (p(meta)=2.23×10(-9)) while for rs1250248, a genome-wide significant p(meta) value of 3.89×10(-9) was detected only in association with severe forms. An epistatic interaction between rs7521902 and rs1250248 (OR 1.56, p=1.19×10(-2)) was found especially in presence of ovarian disease (OR=2.15, p=3.12×10(-4)). CONCLUSIONS: We confirm WNT4, CDKN2BAS and FN1 as the first identified common loci for endometriosis.

Interferon-inducible genes, TNF-related apoptosis-inducing ligand (TRAIL) and interferon inducible protein 27 (IFI27) are negatively regulated in leiomyomas: implications for a role of the interferon pathway in leiomyoma development.

Uterine leiomyomas are the most common tumors in the human female pelvis and the leading indication for pelvic surgery. Lack of understanding of the molecular pathogenesis of leiomyoma has put severe limitations on the availability of alternative treatments. Using an oligonucleotide micro-array-based hybridisation analysis we observed a group of genes with a broad range of functional activity differentially expressed in smooth muscle cells (SMC) derived from leiomyomas when compared to matched myometrial cells. Among them, two IFNα inducible genes, TRAIL and IFI27, were underexpressed in leiomyoma vs. myometrial cells. Expression levels of TRAIL and IFI27 were also measured in myometrial and leiomyoma cells by real-time quantitative PCR in basal condition and after IFNα stimulation. In both cell types, the transcription of the two genes resulted induced by IFNα but the IFI27 transcription stimulation was weaker in leiomyoma than myometrial cells whereas the TRAIL transcription stimulation resulted stronger in leiomyoma respect myometrial cells. Based on this finding and on previous observations we have hypothesized that a reduced response to IFNα stimulation might be involved in leiomyoma formation and growth.

Gene expression profiling of peripheral blood mononuclear cells in endometriosis identifies genes altered in non-gynaecologic chronic inflammatory diseases.

BACKGROUND: Pelvic inflammatory phenomena have been suggested as critical players in the natural history of endometriosis. However, to what extent these events could affect the systemic immunologic status remains to be clarified. Here, we compared the gene expression profile in peripheral blood mononuclear cells from endometriosis patients in the severe diseased stage with the profile after a conventional surgical treatment for removal of endometriotic lesions and adhesions. METHODS: Microarray analysis included four patients suffering from severe endometriosis in which blood samples were obtained few days before the surgical intervention and again 6 months later. Real-time quantitative PCR analyses on a larger population were performed for some genes up-regulated in the diseased stage in a case-control approach. RESULTS: Among the 17,665 probe signals detected in the microarray, n = 26 genes resulted up-regulated and n = 15 were down-regulated in the diseased stage. Five genes up-regulated in diseased stage (FBJ Murine osteosarcoma viral oncogene homolog gene, dual specificity phosphatase 1, pre-B-cell colony enhancing factor 1, adrenomedullin and S100 calcium binding protein P) were exactly those shown as up-regulated in peripheral leukocytes of psoriasis patients in a very similar study design (diseased versus 'cured' stage), with a 5.2 × 10(-11) hypergeometric probability that this event could occur by chance. CONCLUSIONS: Endometriosis induces the expression of genes in peripheral leukocytes already identified in non-gynaecologic chronic inflammatory diseases, thus revealing the disease as a local affliction with relevant consequences at the systemic level. Although the commonality of gene expression with other inflammatory diseases prevents the use of these genes as non-invasive diagnostic markers, from a clinical standpoint, the idea that the surgical intervention may reduce the expression of peripheral leukocyte genes represents a novel finding.

Hormonal therapy potentiates the effect of surgery on gene expression profile of peripheral blood mononuclear cells in patients affected by endometriosis.

BACKGROUND: Combined oral contraceptives (COCs) represent a common pharmacological approach for endometriosis. They have been demonstrated to mitigate painful symptoms in patients and are considered the first line therapy for symptomatic disease. The goal of this study was to evaluate whether the presence of pelvic endometriotic lesions can exert a systemic effect on PBMC gene expression and to investigate whether hormonal treatment may restore a normal gene expression profile. METHODS: Forty women, with endometriosis at stage III-IV, were enrolled in the study. After surgery, 20, randomly chosen, were treated with COC for six months and 20 did not receive hormonal therapy. Blood samples were obtained few days before surgery and six months after surgery. Gene expression profile of PBMC was studied by microarray. Gene expression levels before surgery and post-surgery, in presence and absence of COC, were compared. RESULTS: Nine genes previously reported to be overexpressed by endometriosis, were confirmed to be significantly downregulated after surgery. COC treatment lead to a greater down-regulation of these genes and to a significant down-regulation of 3 additional genes. 145 genes resulted downregulated and 28 upregulated by comparing gene expression before surgery with that 6 months after surgery in the presence of COC therapy. CONCLUSIONS: Results support the concept that a systemic chronic inflammatory status is among the mechanisms underlying endometriosis. Moreover, they shed light into the mechanisms of action of COCs and strength the rationale for their use to improve quality of life of women affected by the disease.

The vascular endothelial growth factor +405G>C polymorphism in endometriosis.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent stimulus of angiogenesis potentially contributing to the pathogenesis of endometriosis. The aim of this study was to investigate the potential association between the single nucleotide polymorphism +405G>C of the VEGF gene with the risk of endometriosis, for the first time in the Caucasian population. METHODS: The polymorphism +405G>C of the VEGF gene was examined in n = 203 Italian women affected by endometriosis and in n = 140 women without laparoscopic evidence of the disease. All the women were genotyped by PCR-restriction fragment length polymorphism from venous blood samples. We then performed a meta-analysis including results from the present study and from the two previously published studies on this topic. RESULTS: The distribution of the three different genotypes significantly differed between women with and without the disease (P = 0.03). The odds ratio (95% confidence interval) for endometriosis in women carrying the C allele was 1.8 (1.2-2.8). The Breslow-Day test revealed statistically significant heterogeneity among the studies performed so far thus indicating inconsistency among studies and excluding the possibility of obtaining a common estimation of the effect. CONCLUSIONS: Results obtained herein are in keeping with those obtained previously and support a role for the +405G>C VEGF polymorphism in endometriosis development, although a further, larger study is required to confirm our findings. However, this effect may depend on the population studied. Ethnicity and the characteristics of endometriosis are likely to influence this association.

Genetics of endometriosis: current status and prospects.

Family and twin studies have shown that heritability accounts for endometriosis development to an extent similar to other complex genetic diseases. Both linkage analysis and association studies have been performed to identify genetic determinants for the disease. Results from the linkage scan of 1,176 families collected thanks to a joint effort between an Australian and a UK group supported significant linkage to a novel susceptibility locus on chromosome 10q26. Although gene variants with effects on the disease predisposition have been proposed to exist and several candidates have been put forward, their effects have not been or are yet to be confirmed. The main categories of candidate genes studied have been those involved in detoxification processes, sex steroid biosynthesis and action, immune system regulation. Genetic studies on endometriosis face numerous challenges as the disease has several manifestations and different forms. Moreover, strong gene-environmental interactions might definitively influence approaches to identify genetic variants involved. Genome-wide association studies that survey most of the genome for causal genetic variants provide the potential for future progress.

Recurrent atypical polypoid adenomyoma and pregnancy: A new conservative approach with levonorgestrel-releasing intrauterine system.

•Levonorgestrel IUD was effective in treatment of recurrent APA.•No side effects were reported.•No impairments on a subsequent pregnancy were reported.

Determinants of long-term clinically detected recurrence rates of deep, ovarian, and pelvic endometriosis.

OBJECTIVE: This study was undertaken to analyze the frequency and the determinants of long-term clinically detectable recurrence rate of deep, ovarian, and pelvic endometriosis. STUDY DESIGN: The clinical data of 1106 women with first diagnosis of endometriosis observed between 1979 and 2001 were collected. RESULTS: The 4-year recurrence rate was 24.6%, 17.8%, 30.6% and 23.7%, respectively, for cases of ovarian, pelvic, deep, and ovarian and pelvic endometriosis (P < .05). The recurrence rates decreased in all groups (with the exception of ovarian endometriosis) in the class age 34 years or older, these findings were significant (P < .05). Radicality was associated with lower recurrence rates in all the groups. A pregnancy after diagnosis was associated with a reduced risk of recurrence. CONCLUSION: The study shows that the recurrence rates of endometriosis were higher in case of deep endometriosis and that the risk factors for recurrence were similar among women with endometriosis at different sites.

Postsurgical ovarian failure after laparoscopic excision of bilateral endometriomas.

OBJECTIVE: This study was undertaken to determine the frequency of postsurgical ovarian failure in patients undergoing laparoscopic excision of bilateral endometriomas. STUDY DESIGN: Patients who had been operated on for bilateral ovarian endometriosis between January 1995 and December 2003 and who were younger than 40 years at the time of surgery were contacted by telephone and interviewed. RESULTS: A total of 126 patients were recruited. Mean +/- SD age of patients at the time of surgery was 30.4 +/- 4.3 years. Postsurgical ovarian failure was documented in 3 cases, corresponding to a rate of 2.4% (95% CI 0.5%-6.8%). In all cases, this complication occurred immediately after surgery. CONCLUSION: Patients who had been operated on for bilateral endometriomas have a low but definite risk of premature ovarian failure occurring immediately after surgery.

Human chorionic gonadotropin level as a predictor of trophoblastic infiltration into the tubal wall in ectopic pregnancy: a blinded study.

OBJECTIVE: To determine the relationship between gestational age, tubal ultrasonographic diameter, and serum hCG levels and different stages of trophoblastic infiltration of the tubal wall in ectopic pregnancy. DESIGN: Blinded prospective study. SETTING: University-based clinic in Italy. PATIENT(S): Thirty-seven consecutive patients with an ampullary ectopic pregnancy. INTERVENTION(S): Laparoscopic salpingectomy. MAIN OUTCOME MEASURE(S): Gestational age, diameter of the tubal mass as determined by transvaginal ultrasonography. and hCG level on the day of surgery. Ectopic pregnancy was classified according to the depth of trophoblastic infiltration: trophoblast limited to the tubal mucosa (stage I), extension to the tubal muscularis (stage II), or complete tubal wall infiltration up to the serosa discontinued by trophoblastic cells (stage III). RESULT(S): Fifteen patients (40.5%) had stage I tubal infiltration, 14 (37.8%) had stage II infiltration, and 8 (21.6%) had stage III infiltration. Gestational age and diameter of the tube did not differ among the three groups. The median hCG level was 1,710.5 mIU/mL (range, 113-5,635 mIU/mL) for patients with stage I infiltration. 4,690.0 mIU/mL (range, 150-21,531 mIU/mL) for patients with stage II infiltration, and 15,700.0 mIU/mL (range, 13,809-21,650 mIU/mL) for patients with stage III infiltration. All the patients with hCG levels > 6,000 mIU/mL had stage II or III invasion. CONCLUSION(S): These findings may explain why the conservative treatment of ectopic pregnancy is less successful in patients with high hCG levels than in patients with low levels. Use of radical procedures may be justified in the former group.

Laparoscopic uterosacral ligament resection for dysmenorrhea associated with endometriosis: results of a randomized, controlled trial.

OBJECTIVE: To evaluate the efficacy of laparoscopic resection of the uterosacral ligaments in women with endometriosis and predominantly midline dysmenorrhea. DESIGN: Randomized controlled trial. SETTING: Two academic departments. One hundred eighty patients undergoing operative laparoscopy as first-line therapy for stage I to IV symptomatic endometriosis. INTERVENTION(S): Operative laparoscopy including uterosacral ligament resection or conservative surgery alone. MAIN OUTCOME MEASURE(S): Proportion of women with recurrence of moderate or severe dysmenorrhea 1 year after surgery. RESULT(S): No complications occurred. Among the patients who were evaluable 1 year after operative laparoscopy, 23 of 78 (29%) women who had uterosacral ligament resection and 21 of 78 (27%) women who had conservative surgery only reported recurrent dysmenorrhea. The corresponding numbers of patients at 3 years were 21 of 59 (36%) women and 18 of 57 (32%) women, respectively. Time to recurrence was similar in the two groups. Pain was substantially reduced, and patients in both groups experienced similar and significant improvements in health-related quality of life, psychiatric profile, and sexual satisfaction. Overall, 68 of 90 (75%) patients in the uterosacral ligament resection group and 67 of 90 (74%) patients in the conservative surgery group were satisfied at 1 year. CONCLUSION(S): Addition of uterosacral ligament resection to conservative laparoscopic surgery for endometriosis did not reduce the medium- or long-term frequency and severity of recurrence of dysmenorrhea.

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.

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.

Pre- and post-treatment patterns of human chorionic gonadotropin for early detection of persistence after a single dose of methotrexate for ectopic pregnancy.

OBJECTIVE: Given the great variability of human chorionic gonadotropin (HCG) levels after a single dose of methotrexate (MTX) for ectopic pregnancy, it remains complicated to identify cases undergoing persistence until a week from treatment. We evaluated whether pre-treatment patterns of HCG levels could be useful for an earlier detection of persistent trophoblast. STUDY DESIGN: A retrospective study on 62 patients treated by a systemic single dose of methotrexate (50 mg/m(2)) for an ectopic pregnancy. Samples for HCG detection were obtained on days -2 and 0 before the therapy, on days +3, +7 and then weekly until values were undetectable. Patients were divided into three groups: Group U (up, meaning "increasing") and Group D (down, meaning "decreasing") when HCG levels on day 0 were respectively higher or lower than day -2 level of more than 20% and Group P (plateau) when the difference between day -2 HCG level and the level on day 0 was less than 20%. RESULTS: All the patients of Group D underwent a complete resolution, with a percentage of 33.3% of cases who underwent an initial rise of HCG levels on day +3. The percentage of cases undergoing an initial rise of HCG levels in Group U patients was significantly higher than in Group P patients (60.0% versus 28.6%), but the resolution rate resulted similar in the two groups. For patients of Group P, an increase of HCG levels on day +3 was significantly correlated to the failure of the therapy. Indeed, comparing the cases with an immediate increase of HCG levels to the cases with immediate decrease of HCG levels on day +3, the persistence rate was 80% for the former and 12% for the latter (P < 0.0001). CONCLUSION: An initial rise of HCG levels after the therapy does not seem to have a clinical relevance in Group D and Group U patients, it well correlates to trophoblastic persistence in Group P patients.

Histologic analysis of specimens from laparoscopic endometrioma excision performed by different surgeons: does the surgeon matter?

OBJECTIVE: To evaluate whether the amount of ovarian tissue inadvertently removed along with the endometrioma cyst wall at laparoscopy differs in relation to the operating surgeon's level of expertise. DESIGN: Multicenter, prospective trial. SETTING: Four tertiary care university hospitals. PATIENT(S): Fifty patients, aged 25 to 40 years, with monolateral ovarian endometriomas who underwent laparoscopic excision. INTERVENTION(S): Operation with the stripping technique by surgeons with specific expertise in endometriosis surgery in four centers (groups A, B, C, and D) and by residents with average training in laparoscopic surgery (group E). MAIN OUTCOME MEASURE(S): Histologic examination for the evaluation of the mean thickness of the cyst wall from each specimen, and the mean thickness and morphologic characteristics of any ovarian tissue removed. RESULT(S): No statistically significant differences were present in the rate of presence of ovarian tissue in the endometrioma wall specimens from the different groups (44%, 45%, 55%, 56%, and 60% in groups A, B, C, D, and E, respectively). For groups A+B+C+D versus group E, a statistically significant difference was found in the mean thickness of the tissue specimens (1.51 mm vs. 1.91 mm, respectively) and in the mean thickness of ovarian tissue inadvertently excised (0.49 mm vs. 0.97 mm, respectively). CONCLUSION(S): Level of expertise in endometriosis surgery is inversely correlated with inadvertent removal of healthy ovarian tissue along with the endometrioma capsule.