Maria Elisabetta Coccia

Endometriosis and infertility

Endometriosis is a debilitating condition characterized by high recurrence rates. The etiology and pathogenesis remain unclear. Typically, endometriosis causes pain and infertility, although 20–25% of patients are asymptomatic. The principal aims of therapy include relief of symptoms, resolution of existing endometriotic implants, and prevention of new foci of ectopic endometrial tissue. Current therapeutic approaches are far from being curative; they focus on managing the clinical symptoms of the disease rather than fighting the disease. Specific combinations of medical, surgical, and psychological treatments can ameliorate the quality of life of women with endometriosis. The benefits of these treatments have not been entirely demonstrated, particularly in terms of expectations that women hold for their own lives. Although theoretically advantageous, there is no evidence that a combination medical-surgical treatment significantly enhances fertility, and it may unnecessarily delay further fertility therapy. Randomized controlled trials are required to demonstrate the efficacy of different treatments.

Complex pelvic mass as a target of evaluation of vessel distribution by color Doppler sonography for the diagnosis of adnexal malignancies: results of a multicenter European study.

Objective. To compare the diagnostic accuracy of gray scale sonography and color Doppler imaging in the differential diagnosis of adnexal malignancies from benign complex pelvic masses in a multicenter prospective study. Methods. The study was performed as a collaborative work at 3 European university departments of obstetrics and gynecology. A total of 826 complex pelvic masses on which transvaginal sonography and evaluation of cancer antigen 125 plasma concentrations were performed before surgical exploration were included in the study. The scanning procedure was the same in the 3 institutions. An adnexal mass was first studied in gray scale sonography, and a probable histologic type was predicted. Second, solid excrescences or solid portions of the tumor were evaluated for vascular flow with color Doppler sonography (conventional or power). A mass was graded malignant if flow was shown within the excrescences or solid areas and benign if there was no flow. The overall agreement between the test result and the actual outcome was calculated by κ statistics. Results. Color Doppler evaluation was more accurate in the diagnosis of adnexal malignancies in comparison with gray scale sonography (κ = 0.82 and 0.65, respectively) because of significantly higher specificity (0.94 versus 0.84; P < .001). The evaluation of the cancer antigen 125 plasma concentration did not seem to increase the accuracy of either method. Conclusions. The evaluation of vessel distribution by color Doppler sonography in complex adnexal cysts seems to increase the diagnostic accuracy of gray scale sonography in the detection of adnexal malignancies in a large study population.

Gynaecological endoscopic evaluation of 4% icodextrin solution: a European, multicentre, double-blind, randomized study of the efficacy and safety in the reduction of de novo adhesions after laparoscopic gynaecological surgery

BACKGROUND Gynaecological laparoscopic surgery outcomes can be compromised by the formation of de novo adhesions. This randomized, double-blind study was designed to assess the efficacy and safety of 4% icodextrin solution (Adept(®)) in the reduction of de novo adhesion incidence compared to lactated Ringers solution (LRS). METHODS Patients undergoing laparoscopic surgery for removal of myomas or endometriotic cysts were treated with randomized solution as an intra-operative irrigant and 1l post-operative instillate. De novo adhesion incidence (number of sites with adhesions), severity and extent were independently scored at a second-look procedure and the efficacy of the two solutions compared. The effect of surgical covariates on adhesion formation was also investigated. Initial exploratory analysis of individual anatomical sites of clinical importance was progressed. RESULTS Of 498 patients randomized, 330 were evaluable (160 LRS--75% myomectomy/25% endometriotic cysts; 170 Adept--79% myomectomy/21% endometriotic cysts). At study completion, 76.2% LRS and 77.6% Adept had ≥ 1 de novo adhesion. The mean (SD) number of de novo adhesions was 2.58 (2.11) for Adept and 2.58 (2.38) for LRS. The treatment effect difference was not significant (P = 0.909). Assessment of surgical covariates identified significant influences on the mean number of de novo adhesions regardless of treatment, including surgery duration (P = 0.048), blood loss in myomectomy patients (P = 0.019), length of uterine incision in myomectomy patients (P < 0.001) and number of suture knots (P < 0.001). There were 15 adverse events considered treatment-related in the LRS patients (7.2%) and 18 in the Adept group (8.3%). Of 17 reported serious adverse events (9 LRS; 8 Adept) none were considered treatment-related. CONCLUSIONS The study confirmed the safety of Adept in laparoscopic surgery. The proportion of patients with de novo adhesion formation was considerably higher than previous literature suggested. Overall there was no evidence of a clinical effect but various surgical covariates including surgery duration, blood loss, number and size of incisions, suturing and number of knots were found to influence de novo adhesion formation. The study provides direction for future research into adhesion reduction strategies in site specific surgery.

Ovarian surgery for bilateral endometriomas influences age at menopause

BACKGROUND Questions remain as to whether surgical excision of ovarian endometriomas might cause damage to ovarian function. To test the hypothesis that ovarian surgery for endometrioma compromises ovarian function and accelerates ovarian failure. METHODS In a tertiary university Clinic, longitudinal prospective cohort study. Patients who underwent laparoscopy for endometriosis between March 1993 and November 2007 were assessed for inclusion in the study. A prospective follow-up at 3, 6 and 12 months then yearly was conducted. Evolution of menstrual pattern, symptoms and reproductive outcomes were investigated. RESULTS From over the 14-year period, 302 patients were included in the study. The mean age (±SD) of patients was 32.6 ± 5.6 years; the median duration of follow-up was 8.5 years (range 2-17 years). Menopause was documented in 43 women (14.3%) at a mean age of 45.3 ± 4.3 years (range 32-52 years). Women previously submitted to bilateral cystectomy were younger at menopause than those with monolateral endometrioma (42.1 ± 5.1 years versus 47.1 ± 3.5 years, P = 0.003). Premature ovarian failure (POF) was observed in 7 of 43 (16.3%) menopausal patients; the majority (4, 57.1%) after bilateral cystectomy. The relationship between the preoperative ovarian endometriomas total diameter and menopausal age was significant in case of surgery for bilateral endometriomas (R(2) = 0.754, P = 0.002). CONCLUSIONS Patients who had been operated on for bilateral endometriomas have an increased risk of POF. Ovarian parenchyma loss at the time of surgery seems related to cyst diameter. In the case of unilateral ovarian endometrioma, the contralateral intact ovary might adequately compensate.

Impact of endometriosis on in vitro fertilization and embryo transfer cycles in young women: a stage-dependent interference

Objective. Endometriosis is a frequent indication for in vitro fertilization and embryo transfer (IVF‐ET). Its influence on IVF‐ET cycles remains controversial. We evaluated the impact of the severity of endometriosis on IVF‐ET cycles in young women. Design. Retrospective cohort study. Setting. Academic tertiary referral centre. Sample and Methods. In a retrospective cohort analysis, 164 IVF‐ET cycles in 148 women with endometriosis‐associated infertility were analyzed. Eighty cycles performed during the same period on 72 consecutive women with tubal infertility were considered as controls. All patients were younger than 35 years old. Main Outcome Measures. Response to controlled ovarian hyperstimulation (COH), number of oocytes retrieved, fertilization, implantation and pregnancy rate (PR). Results. Clinical PR was lower in the group with endometriosis (all stages) in comparison with the tubal factor group. Higher total gonadotropin requirements, lower response to COH and lower oocyte yield were also found in the endometriosis group. Stage‐stratified analysis showed a lower fertilization rate in stage I–II (52.6% stage I–II, 70.5% stage III–IV and 71.9% tubal factor). In stage III–IV endometriosis there was a higher cycle cancellation rate, a reduced response to COH and a lower PR compared with both the stage I–II and the tubal infertility groups (PR 9.7, 25 and 26.1%, respectively). Conclusions. Stage III–IV was strongly associated with poor IVF outcome. A decreased fertilization rate in stage I–II might be a cause of subfertility in these women, owing to a hostile environment caused by the disease.

Hypercoagulability, high tissue factor and low tissue factor pathway inhibitor levels in severe ovarian hyperstimulation syndrome: possible association with clinical outcome

&NA; During ovarian gonadotrophin stimulation for ovulation induction or in vitro fertilization, a clinical severe ovarian hyperstimulation syndrome (OHSS) may occur. Only few studies have investigated the mechanism responsible for the alterations of the haemostatic system in women affected by severe OHSS. The aim of the present study was to investigate the correlation between the magnitude of ovarian stimulation and the increase in fibrin formation and degradation in severe OHSS. Twenty‐five patients (age range 23‐43 years) who were hospitalized for severe OHSS, 25 women undergoing in vitro fertilization who did not develop OHSS (case‐control group) and 25 healthy age‐matched women (healthy control group) were investigated. On the day of admission a number of haemostatic markers, including D‐dimer, thrombin‐antithrombin complexes (TAT), prothrombin fragment 1+2 (F1 + 2), plasmin‐antiplasmin complexes (PAP), tissue factor (TF), tissue factor pathway inhibitor (TFPI) and von Willebrand factor antigen (vWF), were examined. In patients with severe OHSS, TF, D‐dimer, TAT, F1 + 2, PAP and vWF antigen plasma levels were significantly higher than those observed both in the case‐control group and in healthy controls, whereas TFPI levels were significantly lower (P < 0.005) with respect to both case‐controls and healthy controls. D‐Dimer levels were related with serum oestradiol levels and oocyte number recovered (r= 0.45, P < 0.001 and r=0.47, P < 0.001, respectively). D‐Dimer and TAT levels were significantly (P < 0.05 and P < 0.005, respectively) higher in OHSS patients with unsuccessful pregnancy outcome (D‐dimer, 226.5, 56‐1449 ng/ml; TAT, 19.8, 3.1‐82.6 μg/l) with respect to those with successful outcome of pregnancy (D‐dimer, 145, 29‐330 ng/ml; TAT, 5.0, 1.0‐19.6 μg/l). Our data indicate that a marked hypercoagulability with alterations of TF and TFPI levels is detectable in patients with severe OHSS and that it is related to the clinical outcome. Blood Coagul Fibrinolysis

Hormonal patterns, steroid receptors and morphological pictures of endometrium in hyperstimulated IVF cycles

OBJECTIVE The purpose of this contribution is to investigate the pathophysiology of the abnormal endometrial development in hyperstimulated IVF cycles. STUDY DESIGN In 12 IVF-patients who did not have embryo transfer because of failure of oocyte fertilization, serum values of 17 beta-estradiol, progesterone, FSH, LH, total and free testosterone, and androstenedione were measured on the pick-up day and were evaluated with respect to the values normally expressed in the day of ovulation; in the endometrial specimens collected 2 days later, at the time of embryo replacement, estrogen and progesterone receptors were immunohistochemically determined and dating by the Noyes method was performed. RESULTS 17 beta-Estradiol values are constantly higher, and progesterone levels are, only in four cases, higher than expected for the day of ovulation in a natural cycle. These hormonal patterns can only partially explain the pattern of steroid receptors: progesterone receptors are expressed sparsely both in glands and stroma, while estrogen receptors are abundant in the glands and absent in the stroma. In 11 of 12 patients an abnormal endometrial development with stromal advancement was observed: this morphological picture of the endometrium could partially be explained only in the four cases presenting high progesterone levels by serum values and endometrial receptor content of estrogen and progesterone. CONCLUSIONS The abnormal endometrial development in hyperstimulated IVF cycles could only in part be explained by estrogen and progesterone, and other factors have to be considered.

Ultrasonographic staging: a new staging system for deep endometriosis.

Modern imaging techniques allow for the noninvasive diagnosis of endometriosis. Preoperative staging of pelvic endometriosis helps the gynecologist plan therapy and offer a prognosis to patients. The challenge of creating a satisfactory classification of endometriosis remains. The ability of the current classification schemes to predict pregnancy outcome, or aid in the management of pelvic pain, is recognized to be inadequate. The study of deeply infiltrating endometriosis and adenomyosis is greatly hampered by a lack of clear terminology and the absence of a consensus classification of the lesions. A reviewed consensus classification of endometriosis in general, with a more detailed consideration on deep endometriosis, is urgently required. We suggest a new staging system for deep, infiltrating endometriosis based on ultrasonographic findings. Prospective data collection and review in large centers may provide a larger clinical base from which to derive empirical point scores and breakpoints in the classification scheme.

Is there a critical endometrioma size associated with reduced ovarian responsiveness in assisted reproduction techniques

This study investigated the relationships between ovarian endometrioma size, ovarian responsiveness and the number of retrieved oocytes following ovarian stimulation. A prospective study was conducted in a public clinical assisted reproduction centre. A total of 64 infertile women with monolateral endometriomas undergoing IVF or intracytoplasmic sperm injection were included in the study. The total number of follicles, number of follicles ≥ 16 mm and number of oocytes retrieved of ovaries containing endometrioma and normal ovaries were compared. Multivariate linear regression was used to assess whether number of follicles and collected oocytes varied by endometrioma size, age, basal FSH concentration. Significantly lower numbers of follicles ≥ 16 mm (P = 0.024) and oocytes retrieved (P = 0.001) in the ovaries containing endometrioma were observed. In patients with endometriomas ≥ 30 mm, endometrioma size was the most influential contributor to the total number of follicles and oocytes retrieved. Ovarian endometriomas result in reduced response to ovarian stimulation, compared with the response of the contralateral normal ovary in the same individual. In case of endometriomas <30 mm, basal FSH concentration remains the most important prognostic factor for oocyte retrieval.

Pressure lavage under ultrasound guidance: a new approach for outpatient treatment of intrauterine adhesions

OBJECTIVE To present pressure lavage under ultrasound guidance (PLUG) as a new therapeutic procedure for selected cases of intrauterine adhesions (IUA). DESIGN An open clinical investigation with no control group. SETTING Teaching hospital. PATIENT(S) Seven consecutive patients referred to our department for secondary amenorrhea due to IUA. INTERVENTION(S) A newly developed technique based on sonohysterography was used to monitor the effects of intrauterine injections of saline solution on the continuous accumulation of saline in the uterine cavity for the mechanical disruption of IUA. MAIN OUTCOME MEASURE(S) Lysis of intrauterine adhesions, restoration of menses, and increased pregnancy rate in infertile patients. RESULT(S) Five patients with mild IUA obtained satisfactory lysis of adhesions by the use of the PLUG technique. A second-look hysteroscopy after 1 month showed that filmy adhesions persisted in two patients with moderate IUA. These adhesions were removed successfully during hysteroscopy. Restoration of menses was obtained and has continued in all patients. Two of the three infertile patients became pregnant. CONCLUSION(S) This technique is safe and ideal as an in-office procedure. PLUG allows complete lysis in mild IUA cases, and the need for therapeutic, and possibly follow-up hysteroscopy, can be avoided. In moderate IUA cases, the procedure may represent a useful initial step in reducing the need for operative hysteroscopy.