Pier Giorgio Crosignani

Consensus on infertility treatment related to polycystic ovary syndrome

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. This paper describes, on the basis of the currently available evidence, the consensus reached by a group of experts regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counselling should be provided emphasizing the importance of life style, especially weight reduction and exercise in overweight women, smoking and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotrophins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotrophins is associated with increased chances for multiple pregnancy and, therefore, intense monitoring of ovarian response is required. LOS alone is usually effective in <50% of women and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC, gonadotrophin paradigm) is reported to be highly effective with a cumulative singleton live birth rate of 72%. Recommended third-line treatment is in vitro fertilization. More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-, second- or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.

Endometriosis and pelvic pain: relation to disease stage and localization *

OBJECTIVES To determine whether prevalence and severity of pain symptoms are related to endometriosis stage and site, with particular reference to deep infiltrating vaginal lesions. DESIGN Systematic assessment of chronic pelvic pain symptoms. SETTING University hospital endometriosis center. PATIENTS A total of 244 consecutive symptomatic patients with endometriosis diagnosed at laparoscopy or laparotomy. INTERVENTIONS Assessment of dysmenorrhea and nonmenstrual pain by means of a 10-point linear analog scale, a 7-point multidimensional rating scale, and a 3-point verbal scale; evaluation of deep dyspareunia with the first and third systems only. MAIN OUTCOME MEASURES Prevalence and severity of pain symptoms in relation to endometriosis stage and site of lesions. Correlation between revised American Fertility Society score and symptoms severity, as well as between two pain scales to assess dysmenorrhea and nonmenstrual pain. RESULTS Eighty-eight women had stage I and II disease and 156 had stage III and IV disease. Only ovarian endometriosis was present in 108 patients, only peritoneal implants were present in 37, combined ovarian and peritoneal lesions were present in 57, and histologically confirmed vaginal endometriosis was present in 42. The frequency and severity of deep dyspareunia and the frequency of dysmenorrhea were less in patients with only ovarian endometriosis than in those with lesions at other sites. Patients with vaginal endometriosis had a significantly increased risk of deep dyspareunia compared with those whose lesions were at other sites (odds ratio, 2.55; 95% confidence interval, 1.21 to 5.39). Stage per se, independent of lesion site, was not correlated with frequency and severity of dysmenorrhea and nonmenstrual pain. The severity of deep dyspareunia was related inversely to the endometriosis score (Spearman correlation coefficients for linear analog and verbal rating scales, respectively, -0.22 and -0.20). Kendall test by ranks revealed a correlation between linear analog and multidimensional pain scales in the rating of both dysmenorrhea and nonmenstrual pain (respectively, tau-b, 0.59 and tau-b, 0.68). CONCLUSIONS Endometriosis stage in the current classification was not related consistently to pain symptoms. The presence of vaginal lesions was associated frequently with severe deep dyspareunia. Dysmenorrhea and nonmenstrual pelvic pain were assessed with equal accuracy by a linear analog and a multidimensional scale.

Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen

OBJECTIVE To ascertain whether long-term reduction of pain is obtained by continuous administration of an oral contraceptive (OC) in women with endometriosis-associated recurrent dysmenorrhea that does not respond to cyclic OC use. DESIGN Prospective, therapeutic, self-controlled clinical trial. SETTING A tertiary care and referral center for patients with endometriosis. PATIENT(S) Fifty women who underwent surgery for endometriosis in the previous year and experienced recurrent dysmenorrhea despite cyclic OC use. INTERVENTION(S) Continuous use of an OC containing ethinyl estradiol (0.02 mg) and desogestrel (0.15 mg) for 2 years. MAIN OUTCOME MEASURE(S) Dysmenorrhea variation during cyclic and continuous OC use, evaluated with a 100-mm visual analog scale and a 0- to 3-point verbal rating scale, and degree of satisfaction with continuous OC treatment. RESULT(S) In the study period, amenorrhea, spotting, and breakthrough bleeding were reported by 19 (38%), 18 (36%), and 13 (26%) women. The mean +/- SD number of >7-day bleeding episodes with consequent 7-day OC suspension was 5.5 +/- 2.1. The mean +/- SD dysmenorrhea visual analog scale and verbal rating scale scores were 75 +/- 13 and 2.4 +/- 0.5 at baseline and 31 +/- 17 and 0.7 +/- 0.6 at 2-year follow-up, respectively. Moderate or severe side effects were reported by 7/50 (14%) women. At final evaluation, 13 (26%) women were very satisfied, 27 (54%) were satisfied, 1 (2%) was uncertain, 8 (16%) were dissatisfied, and 1 (2%) was very dissatisfied. CONCLUSION(S) Long-term continuous OC use can be proposed to women with symptomatic endometriosis and menstruation-related pain symptoms.

Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study

Abstract Objective To determine whether the frequency and severity of dysmenorrhea are reduced in women with symptomatic endometriosis in whom a levonorgestrel-releasing intrauterine device (Lng-IUD) is inserted after operative laparoscopy compared with those treated with surgery only. Design Open-label, parallel-group, randomized, controlled trial. Setting A tertiary care and referral center for patients with endometriosis. Patient(s) Parous women with moderate or severe dysmenorrhea undergoing first-line operative laparoscopy for symptomatic endometriosis. Intervention(s) Randomization to immediate Lng-IUD insertion or expectant management after laparoscopic treatment of endometriotic lesions. Main outcome measure(s) Proportions of women with recurrence of moderate or severe dysmenorrhea in the two study groups 1 year after surgery and overall degree of satisfaction with treatment. Result(s) Moderate or severe dysmenorrhea recurred in 2 of 20 (10%) subjects in the postoperative Lng-IUD group and 9/20 (45%) in the surgery-only group. Thus, a medicated device inserted postoperatively will prevent the recurrence of moderate or severe dysmenorrhea in one out of three patients 1 year after surgery. A total of 15/20 (75%) women in the Lng-IUD group and 10/20 (50%) in the expectant management group were satisfied or very satisfied with the treatment received. Conclusion(s) Insertion of an Lng-IUD after laparoscopic surgery for symptomatic endometriosis significantly reduced the medium-term risk of recurrence of moderate or severe dysmenorrhea.

Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding

Objective To compare the effect of a levonorgestrel-releasing intrauterine device with that of endometrial resection on menstrual bleeding, patient satisfaction, and quality of life in menorrhagic women during 12 months of followup. Methods Seventy premenopausal women with dysfunctional uterine bleeding were enrolled in a prospective, open, parallel-group, controlled trial. They were randomized to either insertion of an intrauterine system releasing 20 μg/day of levonorgestrel (n = 35) or endometrial resection (n = 35). The women were evaluated at baseline, and thereafter, uterine bleeding was assessed monthly with a pictorial blood loss assessment chart. Clinical gynecologic examination was performed bimonthly, and the hematologic variables were measured at 6 and 12 months. On the latter occasion, the women were requested to rate the degree of satisfaction with the effect of their treatment and to complete the Short Form 36 General Health Survey questionnaire. Results Recurrent menorrhagia was observed at 12 months in four women in the intrauterine device group (including two with partial expulsion of the device) and in three women in the resection group. Compared with baseline values, at 1 year, the pictorial blood loss assessment chart score was reduced by 79% in the former group and by 89% in the latter. Amenorrhea or hypomenorrhea at 12 months was reported by 65% of the women with an intrauterine device compared with 71% who underwent endometrial resection. The degree of satisfaction with treatment was high in both groups, with 29 of 34 (85%) women being satisfied or very satisfied in the intrauterine device group versus 33 of 35 (94%) in the resection group. Health-related quality of life perception was not significantly different in the two treatment groups. Conclusion Somewhat less satisfactory results were obtained with a levonorgestrel-releasing intrauterine system compared with endometrial resection for dysfunctional uterine bleeding at 1 year of follow-up.

The effect of surgery for symptomatic endometriosis: the other side of the story

BACKGROUND Surgery is often considered the best treatment option in women with symptomatic endometriosis. However, extent and duration of the therapeutic benefit are still poorly defined. METHODS The best available evidence on surgery for endometriosis-associated pain has been reviewed to estimate the effect size of interventions in the most frequently encountered clinical conditions. RESULTS Methodological drawbacks limit considerably the validity of observational, non-comparative studies on the effect of laparoscopy for stage I-IV disease. As indicated by the results of three RCTs, the absolute benefit increase of destruction of lesions compared with diagnostic only operation in terms of proportion of women reporting pain relief was between 30% and 40% after short follow-up periods. The effect size tended to decrease with time and the re-operation rate, based on long-term follow-up studies, was as high as 50%. In most case series on excisional surgery for rectovaginal endometriosis, substantial short-term pain relief was experienced by approximately 70-80% of the subjects who continued the study. However, at 1 year follow-up, approximately 50% of the women needed analgesics or hormonal treatments. Major complications were observed in 3-10% of the patients. Medium-term recurrence of lesions was observed in approximately 20% of the cases, and around 25% of the women underwent repetitive surgery. CONCLUSIONS Pain recurrence and re-operation rates after conservative surgery for symptomatic endometriosis are high and probably underestimated. Clinicians and patients should be aware that the expected benefit is operator-dependent.

Progestins for symptomatic endometriosis: a critical analysis of the evidence

OBJECTIVE To obtain estimates of the effects of progestin treatment for pelvic pain associated with endometriosis. DATA IDENTIFICATION Information from studies published in the English-language literature between 1966 and 1996 was pooled. Articles were identified through hand and computerized searches using MEDLINE. STUDY SELECTION A total of 27 trials that were published in peer-reviewed journals were identified, and 13 of these were excluded from the analysis because of methodologic limitations. Nine of the remaining 14 studies were noncomparative (8 prospective and 1 retrospective), 1 was quasi-randomized, and 4 were true randomized controlled trials. DATA EXTRACTION AND SYNTHESIS The sample size was generally limited; the mean number of patients included was 26 in the noncomparative trials and 29 in the randomized controlled trials. The mean duration of treatment was 6 months. A total of 355 women had pain at entry. Considering all noncomparative studies, the pooled frequency of nonresponders at the end of treatment was 9% (18/203; 95% confidence interval [CI], 5.3% to 13.6%). The common odds ratio from the four randomized controlled trials comparing progestins with danazol or a GnRH agonist was 1.1 (95% CI, 0.4 to 3.1), suggesting equivalence in treatment effect. In the only double-blind, placebo-controlled trial, the frequency of nonresponders was not significantly different in the two arms. Only four studies assessed pain after drug withdrawal. The pooled frequency of pelvic pain at the end of follow-up was 50% (35/70; 95% CI, 37.8% to 62.2%). The overall crude conception rate after therapy among women who desired pregnancy was 44% (86/194; 95% CI, 37.2% to 51.6%). Side effects of limited clinical relevance were observed frequently. CONCLUSION(S) The available data suggest that the efficacy of progestins for temporary relief of endometriosis-associated pelvic pain is good and comparable to that of other, less safe treatments.

Surgery for endometriosis-associated infertility: a pragmatic approach

Laparoscopic treatment for endometriosis-associated infertility is gaining widespread popularity supported mostly by uncontrolled studies, but the purported benefit of surgery may be overvalued. We have therefore analysed the best available evidence with the aim of defining an approximate estimate of the effect size of conservative surgery for infertile women with endometriosis in various clinical conditions. The overall increase in post-operative likelihood of conception over background pregnancy rate may be estimated to be between 10 and 25%. The effect of surgery for peritoneal lesions is limited, and an estimate of benefit should be decreased by the fact that preoperative identification of the subjects actually with the condition is unfeasible. The benefit of excision of ovarian endometriomas is difficult to define due to multiple confounding factors and methodological drawbacks in the considered studies. Excision of rectovaginal endometriosis is of doubtful value and associated with worrying morbidity. The role of surgery before, after or as an alternative to IVF needs clarification. In conclusion, the absolute benefit increase of surgery for endometriosis-associated infertility appears smaller than previously believed. Complete and detailed information on risks and benefits of treatment alternatives must be offered to infertile patients to allow unbiased choices between possible options.

Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis

OBJECTIVE To evaluate the efficacy and safety of cyproterone acetate versus an oral contraceptive in the treatment of endometriosis-associated recurrent pelvic pain. DESIGN Randomized controlled trial. SETTING Academic center. PATIENT(S) Ninety women with recurrent moderate or severe pelvic pain after conservative surgery for symptomatic endometriosis. INTERVENTION(S) Six months of continuous treatment with oral cyproterone acetate, 12.5 mg/d, or an oral contraceptive containing ethinyl estradiol, 0.02 mg, and desogestrel, 0.15 mg. MAIN OUTCOME MEASURE(S) Degree of satisfaction with therapy. RESULT(S) Six patients in the cyproterone acetate arm and nine in the oral contraceptive arm withdrew because of side effects (n = 9), treatment inefficacy (n = 4), or loss to follow-up (n = 2). At 6 months, dysmenorrhea, deep dyspareunia, and nonmenstrual pelvic pain scores were substantially reduced, and significant improvements were observed in health-related quality-of-life, psychiatric profile, and sexual satisfaction; no major between-group differences were seen. Subjective and metabolic side effects were limited. According to an intention-to-treat analysis, 33 of 45 (73%) of patients in the cyproterone acetate group and 30 of 45 (67%) in the oral contraceptive group were satisfied with the treatment received. CONCLUSIONS Both cyproterone acetate and a continuous monophasic oral contraceptive were effective, safe, and inexpensive therapy for recurrent pain after conservative surgery for endometriosis.

Laparoscopy versus laparotomy in conservative surgical treatment for severe endometriosis.

OBJECTIVE To determine the outcome of laparoscopy compared with laparotomy in conservative surgical treatment for severe endometriosis. DESIGN Comparison of nonrandomized historical surgical series. SETTING Two teaching hospitals and referral centers specializing in reparative and reconstructive surgery. PATIENT(S) A total of 216 patients operated for severe endometriosis during a 5-year period. INTERVENTION(S) Conservative surgical treatment at laparoscopy (n = 67) or laparotomy (n = 149) with median follow-up of 24 months. MAIN OUTCOME MEASURE(S) Cumulative probability of pregnancy in previously infertile patients (22 in the laparoscopy group and 70 in the laparotomy group) and cumulative probability of pain recurrence in subjects with moderate or severe symptoms before surgery (47 in the laparoscopy group and 108 in the laparotomy group). RESULT(S) The 24-month cumulative probability of pregnancy according to the Kaplan-Meier method was 44.9% after laparoscopy and 62.7% after laparotomy. The 24-month cumulative probability of symptoms recurrence evaluated with a 0 to 3 point verbal rating scale was, respectively, 16.4% versus 20.3% for dysmenorrhea, 33.3% versus 15.4% for deep dyspareunia, and 25.0% versus 15.9% for nonmenstrual pain. The corresponding figures obtained with a 10-point linear analogue scale were 20.3% versus 24.7%, 28.6% versus 10.4%, and 17.5% versus 20.1%. No difference is statistically significant. CONCLUSION(S) Laparoscopy and laparotomy seem equally effective in the treatment of infertility and chronic pelvic pain associated with severe endometriosis. However, a trend was observed toward a higher pregnancy rate and lower dyspareunia recurrence rate after surgery for severe endometriosis performed at laparotomy compared with laparoscopy.