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Vercellini P.,University of Milan | Crosignani P.,University of Milan | Somigliana E.,Infertility Unit | Vigan P.,Center For Research In Obstetrics And Gynaecology Crog | And 2 more authors.
Human Reproduction | Year: 2011

Conservative surgical treatment for symptomatic endometriosis is frequently associated with only partial relief of pelvic pain or its recurrence. Therefore, medical therapy constitutes an important alternative or complement to surgery. However, no available compound is cytoreductive, and suppression instead of elimination of implants is the only realistic objective of pharmacological intervention. Because this implies prolonged periods of treatments, only medications with a favourable safety/tolerability/efficacy/cost profile should be chosen. In the past few years, innumerable new drugs for endometriosis, which would interfere with several hypothesized pathogenic mechanisms, have been studied and their use foreseen. However, robust evidence of in vivo safety and efficacy is lacking and, at the moment, the principal modality to interfere with endometriosis metabolism is still hormonal manipulation. Regrettably, in spite of consistent demonstration of a major effect on pain even in patients with deeply infiltrating lesions, progestins are underestimated and dismissed in favour of more scientifically fashionable and up-to-the-minute alternatives. Moreover, oral contraceptives (OCs) dramatically reduce the rate of post-operative endometrioma recurrence and should now be considered an essential part of long-term therapeutic strategies in order to limit further damage to future fertility. Finally, women who have used OC for prolonged periods will be protected from an increased risk of endometriosis-associated ovarian cancer. To avoid the several subtle modalities for distorting facts and orientating opinions in favour of specific compounds, progestins and monophasic OC used continuously are here proposed as the reference comparator in all future randomized controlled trials on medical treatment for endometriosis. © 2010 The Author.


Vercellini P.,University of Milan | Vercellini P.,Center For Research In Obstetrics And Gynaecology Crog | Somigliana E.,Center For Research In Obstetrics And Gynaecology Crog | Somigliana E.,Infertility Unit | And 5 more authors.
Reproductive BioMedicine Online | Year: 2010

Prevention of the recurrence of post-operative endometriosis is crucial for future fertility. The incidence of disease relapse can be influenced by major demographic changes and by the use of long-term adjuvant medical treatment. Decrease in age at menarche, number of pregnancies and duration of breastfeeding and increase in age at first birth all lead to an increase in the overall number of ovulations and menstruations a woman has within a reproductive lifespan. These changes impact during the decade at highest risk for endometriosis, i.e. between 25 and 35 years of age, and may substantially expand the hiatus between first-line surgical treatment and conception attempt. Several lines of evidence suggest that ovulation inhibition reduces the risk of endometriosis recurrence. After pooling the results of a cohort and a randomized controlled trial on long-term post-operative oral contraceptive use, a recurrent endometrioma developed in 26/250 regular users (10%; 95% CI 7-15%) compared with 46/115 never users (40%; 95% CI 31-50%), with a common OR of 0.16 (95% CI 0.04-0.65). After first-line surgery for endometriosis, women should be invited to seek conception as soon as possible. Alternatively, oral contraceptive use until pregnancy is desired should be considered. © 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Vercellini P.,University of Milan | Vercellini P.,Center For Research In Obstetrics And Gynaecology Crog | Eskenazi B.,University of California at Berkeley | Consonni D.,Unit of Epidemiology | And 6 more authors.
Human Reproduction Update | Year: 2011

Background: Combined oral contraceptives (OCs) inhibit ovulation, substantially reduce the volume of menstrual flow and may hypothetically interfere with implantation of refluxed endometrial cells. The aim of this review is to establish if OC use influences the risk of endometriosis. Methods: We performed a MEDLINE search to identify all studies published in the last four decades (January 1970 to January 2010) in the English language on the relationship between OC exposure and risk of endometriosis. Two authors abstracted data on standardized forms. Results: We identified 608 potentially relevant studies and 18 studies (6 cross-sectional, 7 case-control and 5 cohort) were selected. Pooling of the results derived from all the included reports independently from study design, yielded a common relative risk of 0.63 [95% confidence interval (CI), 0.47-0.85] for current OC users, 1.21 (95% CI, 0.94-1.56) for past users and 1.19 (95% CI, 0.89-1.60) for ever users. Methodological drawbacks, such as uncertain temporal relationship between exposure and outcome in cross-sectional studies and suboptimal selection of controls in case-control studies, limit the quality of the available evidence. Conclusions: The risk of endometriosis appears reduced during OC use. However, it is not possible to exclude the possibility that the apparent protective effect of OC against endometriosis is the result of postponement of surgical evaluation due to temporary suppression of pain symptoms. Confounding by selection and indication biases may explain the trend towards an increase in risk of endometriosis observed after discontinuation, but further clarification is needed. To date, the hypothesis of recommending OCs for primary prevention of endometriosis does not seem sufficiently substantiated. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Vercellini P.,University of Milan | Vercellini P.,Center For Research In Obstetrics And Gynaecology Crog | Consonni D.,Epidemiology Unit | Barbara G.,University of Milan | And 5 more authors.
Reproductive BioMedicine Online | Year: 2014

The relationship between rectovaginal-bowel endometriosis and fertility is unclear. Nevertheless, extirpative surgery, including colorectal resection, is being fostered as a fertility-enhancing procedure. Adenomyosis and deep endometriosis often coexist. As the uterine condition may further impact on reproductive outcome, this work performed a systematic literature review with the objective of identifying all English-language reports on surgical treatment for rectovaginal and colorectal endometriosis, including bowel resection, in which participants were screened preoperatively for uterine adenomyosis. Risk ratios (RR) were then combined in a meta-analysis. In the five selected observational studies, in women seeking pregnancy, 7/59 (11.9%) with concomitant adenomyosis conceived, compared with 74/172 (43.0%) in those without adenomyosis. Adenomyosis was never excised. One in 10 women experienced a major surgical complication. The RR of clinical pregnancy ranged from 0.23 to 0.46, with absence of heterogeneity among studies (I2 = 0.0%). Pooling of the results yielded a common RR of 0.32 (95% confidence interval 0.16 to 0.66). No small-study effect was detected (Egger's test). Screening for adenomyosis before suggesting difficult and risky procedures may allow identification of a subgroup of patients at particularly worse prognosis for which surgery would have a marginal effect on the likelihood of conception. Deep endometriosis may infiltrate the rectum, vagina and sigmoid colon. These severe forms are usually associated with pain, but their relationship with fertility is unclear. Despite lack of convincing evidence, extirpative surgery, including colorectal resection, is being fostered as a fertility-enhancing procedure, although these procedures may cause major complications. Adenomyosis (i.e. the infiltration of the uterine wall by endometrial glands) often coexists with deep endometriosis, and several investigators believe that the former condition may have a detrimental effect on fertility more than the latter. If this is true, screening for adenomyosis may allow preoperative identification of a subgroup of patients at particularly worse prognosis for whom difficult and risky surgery would have a marginal or no effect on the likelihood of conception. To disentangle this issue, we performed a systematic literature review with the objective of identifying all English-language reports on surgical treatment for rectovaginal and colorectal endometriosis, including bowel resection, in which participants were also investigated preoperatively for uterine adenomyosis. Risk ratios (RR) were then combined in a meta-analysis. In the five selected observational studies, in women seeking pregnancy, 7/59 (11.9%) women with concomitant adenomyosis conceived, compared with 74/172 (43.0%) in those without adenomyosis. One in 10 women experienced a major surgical complication. The RR of clinical pregnancy consistently ranged from 0.23 to 0.46. Pooling of the results yielded a common RR of 0.32 (95% CI 0.16-0.66). Adenomyosis was associated with a 68% reduction in the likelihood of pregnancy in women seeking conception after surgery for rectovaginal and colorectal endometriosis. © 2014, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Vercellini P.,University of Milan | Vercellini P.,Center For Research In Obstetrics And Gynaecology Crog | Consonni D.,Epidemiology Unit | Dridi D.,University of Milan | And 5 more authors.
Human Reproduction | Year: 2014

STUDY QUESTION: Is adenomyosis associated with IVF/ICSI outcome in terms of clinical pregnancy rate? SUMMARY ANSWER: In a meta-analysis of published data, women with adenomyosis had a 28% reduction in the likelihood of clinical pregnancy at IVF/ICSI compared with women without adenomyosis. WHAT IS KNOWN ALREADY: Estimates of the effect of adenomyosis on IVF/ICSI outcome are inconsistent. STUDY DESIGN, SIZE, DURATION: A systematic literature review and meta-analysis were conducted. A Medline search was performed to identify all the comparative studies published from January 1998 to June 2013 in the English language literature on IVF/ICSI outcome in women with and without adenomyosis. Two authors independently performed the literature screening, scrutinized articles of potential interest, selected relevant studies and extracted data. Studies were categorized based on research design.PARTICIPANTS, SETTING, METHODSOf the 17 articles assessed in detail, 9 were finally selected based on diagnosis of adenomyosis at magnetic resonance imaging or transvaginal ultrasonography. The quality of studies was evaluated by means of the Newcastle-Ottawa scale. A total of 1865 women were enrolled in the 9 selected studies, 665 of whom in 4 prospective observational studies, and 1200 in 5 retrospective studies. The dichotomous data for clinical pregnancy and secondary outcomes were expressed as risk ratios (RR) with 95% confidence intervals (CIs) and were combined in a meta-analysis using the random-effects model. The heterogeneity Cochrane's Q and the I2 statistics were calculated. Egger's approach to testing the significance of funnel plot asymmetry was also used. MAIN RESULTS AND THE ROLE OF CHANCE: The clinical pregnancy rate achieved after IVF/ICSI was 123/304 (40.5%) women with adenomyosis versus 628/1262 (49.8%) in those without adenomyosis. The RR of clinical pregnancy ranged from 0.37 (95% CI, 0.15-0.92) to 1.20 (95% CI, 0.58-2.45), with a significant heterogeneity among studies (I2 = 56.8%, P = 0.023). Pooling of the results yielded a common RR of 0.72 (95% CI, 0.55-0.95). A funnel plot showed no indication of asymmetry among studies (Egger's test, P = 0.696). In a meta-regression model, no association was observed between prevalence of endometriosis and the likelihood of clinical pregnancy. Three studies reported the pregnancy rate per cycle. The common RR was 0.71 (95% CI, 0.51-0.98; I 2 = 78.1%, P = 0.010). The RR observed in a study with donated oocytes was 0.90 (95% CI, 0.75-1.08). The number of miscarriages per clinical pregnancy was reported in seven studies. A miscarriage was observed in 77/241 women with adenomyosis (31.9%) and in 97/687 in those without adenomyosis (14.1%). The RR of miscarriage ranged from 0.57 (95% CI, 0.15-2.17) to 18.00 (95% CI, 4.08-79.47) (I2 = 67.7%, P = 0.005). Pooling of the results yielded a common RR of 2.12 (95% CI, 1.20-3.75).LIMITATIONS, REASONS FOR CAUTIONQualitative and quantitative heterogeneity among studies was high. At sensitivity analysis, I2 statistic regarding the main outcome was reduced under the 50% threshold removing one trial, but the resulting confidence interval crossed unity. Also the confidence interval of the common RR of the four studies reporting only one IVF/ICSI cycle included unity. Only part of the studies could be included in the assessment of secondary outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Adenomyosis appears to impact negatively on IVF/ICSI outcome owing to reduced likelihood of clinical pregnancy and implantation, and increased risk of early pregnancy loss. Screening for adenomyosis before embarking on medically assisted reproductive procedures should be encouraged. The potentially protective role of long down-regulation protocols needs further evaluation. In future studies on the association between adenomyosis and IVF/ICSI outcome, a matched case-control design should be adopted, live birth should be the default primary outcome and only the results regarding the first cycle should be considered. © 2014 The Author.

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