Bruno Borghese

Endometriosis and infertility: pathophysiology and management

Endometriosis and infertility are associated clinically. Medical and surgical treatments for endometriosis have different effects on a womans chances of conception, either spontaneously or via assisted reproductive technologies (ART). Medical treatments for endometriosis are contraceptive. Data, mostly uncontrolled, indicate that surgery at any stage of endometriosis enhances the chances of natural conception. Criteria for non-removal of endometriomas are: bilateral cysts, history of past surgery, and altered ovarian reserve. Fears that surgery can alter ovarian function that is already compromised sparked a rule of no surgery before ART. Exceptions to this guidance are pain, hydrosalpinges, and very large endometriomas. Medical treatment-eg, 3-6 months of gonadotropin-releasing hormone analogues-improves the outcome of ART. When age, ovarian reserve, and male and tubal status permit, surgery should be considered immediately so that time is dedicated to attempts to conceive naturally. In other cases, the preference is for administration of gonadotropin-releasing hormone analogues before ART, and no surgery beforehand. The strategy of early surgery, however, seems counterintuitive because of beliefs that milder non-surgical options should be offered first and surgery last (only if initial treatment attempts fail). Weighing up the relative advantages of surgery, medical treatment and ART are the foundations for a global approach to infertility associated with endometriosis.

Preoperative work-up for patients with deeply infiltrating endometriosis: transvaginal ultrasonography must definitely be the first-line imaging examination

BACKGROUND Transvaginal ultrasonography (TVUS) has important advantages compared with transrectal ultrasonography (TRUS): it is less invasive, is cost-effective, is a familiar and well-accepted approach, and anesthesia is not required. We compared the accuracy of TVUS and TRUS for diagnosing rectal wall involvement in patients presenting with histologically proved deeply infiltrating endometriosis (DIE). METHODS Prospective study of 134 patients with histologically proved DIE underwent preoperative investigations using both TVUS and TRUS. The radiologist (TVUS) and sonographer (TRUS) were unaware of the clinical findings but knew that DIE was suspected. RESULTS DIE was confirmed histologically for all the patients. A rectal wall involvement was histologically proved for 75 patients (56%). For the diagnosis of infiltration of the intestinal wall, TVUS and TRUS, respectively, had a sensitivity of 90.7% and 96.0%, a specificity of 96.5% and 100.0%, a positive predictive value of 97.1% and 100.0% and a negative predictive value of 88.9% and 95.2%. CONCLUSIONS TVUS and TRUS have similar degrees of accuracy for predicting intestinal involvement. TVUS must be the first-line imaging process to perform for patients presenting with clinically suspected DIE. The question for the coming years is to define if it is necessary for TRUS to be carried out systematically in cases of clinically suspected DIE.

Complete Surgery for Low Rectal Endometriosis: Long-term Results of a 100-Case Prospective Study

Objective:We conducted a prospective study to assess the long-term results of complete surgery for low rectal endometriosis (LRE), paying particular attention to surgical complications, functional results, and disease recurrence after a follow-up of at least 5 years. Summary Background Data:Deep infiltrating endometriosis (DIE) may infiltrate the midlow rectum and lead to severe pelvic pain. Complete resection of LRE is reluctantly considered by young women of childbearing age. Methods:From 1995 to 2003, 100 women with severe pelvic pain and previous incomplete surgery (n = 82) underwent complete open surgery for LRE after thorough preoperative imaging work-up. This included total or subtotal rectal excision with combined resection of all extrarectal endometriotic lesions. Univariate analysis of predictive factors for transient neurogenic bladder and surgical complications was performed. Mean follow-up was 78 ± 15 months. Results:All patients underwent rectal resection with straight coloanal (n = 16) or low colorectal anastomosis (n = 84). A concomitant extrarectal procedure was required in all instances, including gynecologic procedures (n = 100), additional intestinal (n = 45), and urologic (n = 23) resections. A fertility-preserving procedure was possible in 92% of the patients. Mean numbers of DIE and endometriotic lesions were 3.9 ± 1.4 and 5.5 ± 1.6 per patient, respectively. There were no deaths and the surgical morbidity rate was 16%. Sixteen patients developed a transient peripheral neurogenic bladder, which was more frequently observed after colonanal anastomosis (P < 0.001) or concomitant hysterectomy (P < 0.01) and in patients with more than 4 DIE lesions (P < 0.05). At last follow-up, 94 patients had complete (n = 83) or very satisfactory (n = 11) relief of symptoms. Urine voiding and fecal continence was satisfactory in all cases. There was no recurrence of colorectal and/or urologic endometriosis and the overall DIE recurrence rate was 2%. Conclusions:Complete surgery for LRE provides excellent long-term functional results in 94% of the patients, provided all extraintestinal endometriotic lesions are resected during the same surgical procedure. In that setting, the overall 5-year recurrence rate is very low.

Surgery for bladder endometriosis: long-term results and concomitant management of associated posterior deep lesions

BACKGROUND Deep infiltrating endometriosis (DIE) is presented as a disease with high recurrence risk. Bladder DIE is the most frequent location in cases of urinary endometriosis. Surgical removal has been recommended for bladder DIE but long-term outcomes remains unevaluated. The objectives of this study are to evaluate the rate of recurrence after partial cystectomy for patients presenting with bladder DIE and to outline the surgical modalities for handling associated posterior DIE nodules. METHODS Seventy-five consecutive patients with histologically proved bladder DIE were enrolled at a single tertiary academic center between June 1992 and December 2007. A partial cystectomy was performed for each patient. Complete surgical exeresis of all associated symptomatic DIE lesions was carried out during the same surgical procedure. Bladder DIE patients were classified into three groups: patients with isolated bladder DIE (Group A); patients with associated symptomatic posterior DIE (Group B); patients with associated asymptomatic posterior DIE (Group C). Bladder DIE recurrence was defined as a clinical reappearance of the disease or radiological evidence that mandated a new surgical procedure. We assessed pelvic pain symptoms pre- and post-operatively using a 10-cm visual analogue scale. RESULTS In a series of 627 patients with DIE, we observed 75 patients (12%) with bladder DIE. With a 50.9 +/- 44.6 months mean follow-up after partial cystectomy no patient presented evidence of bladder DIE recurrence. Post-operatively, we observed a significant improvement with respect to pain symptoms, with only two patients (2.7%) developing major complications during follow-up. Among patients with non-operated associated asymptomatic posterior DIE lesions (n = 15), a second surgical procedure indicated for pain symptoms was necessary in only one patient (6.7%). CONCLUSIONS For patients presenting with bladder DIE, no patients required further surgery for bladder recurrence after radical surgery consisting in partial cystectomy. Exeresis of associated posterior DIE nodules is indicated only when they are symptomatic.

Gene expression profile for ectopic versus eutopic endometrium provides new insights into endometriosis oncogenic potential.

Endometriosis is a common gynecological disorder characterized by pain and infertility, where the lesions disseminate everywhere in the body with a preference for the pelvis. In that, it could be regarded as a benign metastatic disease, because its issue is not fatal. However, the molecular bases of this intriguing clinical condition are not well known. The objective of this study is to characterize the transcriptome differences between eutopic vs. ectopic endometrium with a special interest in pathways involved in cancerogenesis. We performed two hybridizations in technical replicate on highly specific long oligonucleotides microarrays (NimbleGen), with cDNA prepared from six-patients pools, where the same patient provided both eutopic and ectopic endometrium (endometriomas). To confirm the expression microarrays data, quantitative RT-PCR validation was performed on 12 individuals for 20 genes. Over 8000 transcripts were significantly modified (more than twice) in the lesions corresponding to 5600 down- or up-regulated genes. These were clustered through DAVID Bioinformatics Resources into 55 functional groups. The data are presented in a detailed and visual way on 24 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways implemented with induction ratios for each differentially expressed gene. An outstanding control of the cell cycle and a very specific modulation of the HOX genes were observed and provide some new evidence on why endometriosis only very rarely degenerates into cancer. The study constitutes a noteworthy update of gene profiling in endometriosis, by delivering the most complete and reliable list of dysregulated genes to date.

Associated ovarian endometrioma is a marker for greater severity of deeply infiltrating endometriosis

OBJECTIVE To investigate whether an associated ovarian endometrioma is a marker for severity of deep infiltrating endometriosis (DIE). DESIGN Observational study between June 1992 and December 2005. SETTING University tertiary referral center. PATIENT(S) Five hundred patients with histologically assessed DIE. INTERVENTION(S) Complete surgical exeresis of deep endometriotic lesions. MAIN OUTCOME MEASURE(S) Severity of the disease was quantified according to the mean number of DIE lesions and the type of main lesion. RESULT(S) In patients with associated ovarian endometrioma, the number of single isolated DIE lesions was statistically significantly lower (41.9% vs. 61.1%). The mean number of DIE lesions was statistically significantly higher in patients presenting with an associated ovarian endometrioma (2.51 +/- 1.72 vs. 1.64 +/- 1.0). For patients with associated ovarian endometrioma DIE lesions were more severe with an increased rate of vaginal, intestinal, and ureteral lesions. CONCLUSION(S) Associated ovarian endometrioma is a marker for the severity of the DIE. In a clinical context suggestive of DIE, when there is an ovarian endometrioma, the practitioner should investigate the extent of the disease to check for severe and multifocal DIE lesions.

Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis

BACKGROUND The relationship between the use of oral contraception (OC) and endometriosis remains controversial. We therefore compared various characteristics of OC use and the surgical diagnosis of endometriosis histologically graded as superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) or deep infiltrating endometriosis (DIE). METHODS This cross-sectional study included 566 patients without visible endometriosis at surgery as controls, and 410 patients with histologically proven endometriosis, categorized by their worst lesions as SUP n = 47, OMA n = 120 and DIE n = 243. Personal data, including on OC use, were prospectively collected during standardized interviews. Statistical analysis was performed using unconditional logistic regression. RESULTS Past OC users had an increased incidence of endometriosis (adjusted odd ratios (OR) = 2.79, 95% confidence interval (CI) 1.74-5.12, P = 0.002) of any revised American Fertility Society stage. Women who had previously used OC for severe primary dysmenorrhea were even more frequently diagnosed with endometriosis (adjusted OR = 5.6, 95% CI 3.2-9.8), especially for DIE (adjusted OR = 16.2, 95% CI 7.8-35.3). Women who had previously used OC for other reasons also had an increased risk of endometriosis, but to a lesser extent (adjusted OR = 2.6, 95% CI 1.8-4.1). The age at which OC was initiated, duration of OC use and free interval from last OC use were not significantly different between control and endometriosis women, irrespective of histological grading. Current OC users did not show an increased prevalence of endometriosis (OR = 1.22, 95% CI 0.6-2.52). CONCLUSIONS Our data indicate that a history of OC use for severe primary dysmenorrhea is associated with surgical diagnosis of endometriosis, especially DIE, later in life. However, this does not necessarily mean that use of OC increases the risk of developing endometriosis. Past use of OC for primary dysmenorrhea may serve as a marker for women with endometriosis and DIE.

Questioning patients about their adolescent history can identify markers associated with deep infiltrating endometriosis

OBJECTIVE To investigate whether the clinical history, particularly of the adolescence period, contains markers of deeply infiltrating endometriosis (DIE). DESIGN Cross-sectional study. SETTING Universitary tertiary referral center. PATIENT(S) Two hundred twenty-nine patients operated on for endometriosis. Endometriotic lesions were histologically confirmed as non-DIE (superficial peritoneal endometriosis and/or ovarian endometriomas) (n = 131) or DIE (n = 98). INTERVENTION(S) Surgical excision of endometriotic lesions with pathological analysis of each specimens. MAIN OUTCOME MEASURE(S) Epidemiological data, pelvic pain scores, family history of endometriosis, absenteeism from school during menstruation, oral contraceptive (OC) pill use. RESULT(S) Patients with DIE had significantly more positive family history of endometriosis (odds ratio [OR] = 3.2; 95% confidence interval [CI]: 1.2-8.8) and more absenteeism from school during menstruation (OR = 1.7; 95% CI: 1-3). The OC pill use for treating severe primary dysmenorrhea was more frequent in patients with DIE (OR = 4.5; 95% CI: 1.9-10.4). Duration of OC pill use for severe primary dysmenorrhea was longer in patients with DIE (8.4 ± 4.7 years vs. 5.1 ± 3.8 years). There was a higher incidence of OC pill use for severe primary dysmenorrhea before 18 years of age in patients with DIE (OR = 4.2; 95% CI: 1.8-10.0). CONCLUSION(S) The knowledge of adolescent period history can identify markers that are associated with DIE in patients undergoing surgery for endometriosis.

Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis

BACKGROUND The objective of this study was to evaluate the significance of severe preoperative pain for patients presenting with ovarian endometrioma (OMA). METHODS Three hundred consecutive patients with histologically proven OMA were enrolled at a single university tertiary referral centre between January 2004 and May 2010. Complete surgical excision of all recognizable endometriotic lesions was performed for each patient. Pain intensity was assessed with a 10-cm visual analogue scale (VAS). Pain was considered as severe when VAS was ≥ 7. Prospective preoperative assessment of type and severity of pain symptoms (VAS) was compared with the peroperative findings (surgical removal and histological analysis) of endometriomas and associated deeply infiltrating endometriosis. Correlations were sought with univariate analysis and a multiple regression logistic model. RESULTS After multiple logistic regression analysis, uterosacral ligaments involvement was related with a high severity of chronic pelvic pain [odds ratios (OR) = 2.1; 95% confidence interval (CI): 1.1-4.3] and deep dyspareunia (OR = 2.0; 95% CI: 1.1-3.5); vaginal involvement was related with a higher intensity of lower urinary symptoms (OR = 13.4; 95% CI: 3.2-55.8); intestinal involvement was related with an increased severity of dysmenorrhoea (OR = 5.2; 95% CI: 2.7-10.3) and gastro-intestinal symptoms (OR = 7.1; 95% CI: 3.3-15.3). CONCLUSIONS In case of OMA, severe pelvic pain is significantly associated with deeply infiltrating lesions. In this situation, the practitioner should perform an appropriate preoperative imaging work-up in order to evaluate the existence of associated deep nodules and inform the patient in order to plan the surgical intervention strategy.

An update on the pharmacological management of endometriosis

Introduction: Endometriosis is a common disease that causes pain symptoms and/or infertility in women in their reproductive years. The disease is characterised by the presence of endometrium-like tissue – glands and stroma – outside the uterine cavity. Different treatment options exist for endometriosis including medical and surgical treatments or a combination of the two approaches. The most commonly used medications are non-steroidal anti-inflammatory drugs, GnRH agonists, androgen derivatives such as danazol, combined oral contraceptive pills, progestogens and more recently the levonorgestrel intrauterine system. Areas covered: The authors review current medical treatments used for symptomatic endometriosis and also discuss new treatment approaches. The authors conducted a literature search for randomised controlled trials related to medical treatments of endometriosis in humans, searched the Cochrane library for reviews and also searched for registered trials that have not yet been published on ClinicalTrials.gov. Expert opinion: The medical treatment of endometriosis is effective at treating pain and preventing recurrence of disease after surgery. Remarkably, the oral contraceptive pill taken continuously is as effective as GnRH-a, while causing far less side-effects. Conversely, no treatment currently exists for enhancing fecundity in women whose infertility is associated with endometriosis. As all existing therapies of endometriosis are contraceptive, great efforts should be targeted at researching novel products that reduce the disease expression without shuttering ovulation.