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Objective To employ protocols of mild ovarian stimulation to prevent an excessively elevated rate of high-order multiple pregnancies. Design Case series. Setting University hospital. Patient(s) Six hundred and twenty one consecutive patients undergoing 1,259 controlled ovarian hyperstimulation and intrauterine insemination cycles. Intervention(s) Patients received 50 IU per day of recombinant follicle-stimulating hormone (FSH) starting the third day of the cycle, then a gonadotropin-releasing hormone (GnRH) antagonist on the day in which a follicle ≥13 mm was visualized. Cycles were canceled if three or more follicles ≥16 mm and/or five or more follicles ≥11 mm were detected. Main Outcome Measure(s) Rate of high-order multiple pregnancies. Result(s) The clinical pregnancy rate per initiated cycle was 9.2% (95% confidence interval, 7.5–11.1%). The incidence of twins and high-order multiple pregnancies was 9.5% (95% CI, 5.3–16.2%) and 0 (0.0–3.2%), respectively. Conclusion(s) In controlled ovarian hyperstimulation and intrauterine insemination cycles, a protocol of 50 IU of recombinant FSH daily combined with the use of GnRH antagonists and a policy of strict cancellation based on echographic criteria are associated with a satisfactory pregnancy rate per initiated cycle and a low risk of high-order multiple pregnancies.

Laparoscopic surgery is often carried out in women with endometriosis who experience dysmenorrhea. The results are not consistently good, and affected women often have recurrent pain. This open-label, parallel-group, randomized trial evaluated an intrauterine device (IUD) that releases levonorgestrel (a Lng-IUD), a potent 19-nortestosterone derivative progestin that can induce amenorrhea. Twenty parous women with endometriosis and moderate or severe dysmenorrhea received the Lng-IUD after operative laparoscopy, whereas 20 others had only surgery. The participants, who were 40 years of age or younger and did not want a child, were reevaluated after 12 months. Conservative surgery was performed using only mechanical instruments and electrosurgery. Adhesions were sectioned, the ovaries were mobilized, and areas of endometriosis were either excised or coagulated. The Lng-IUD that was inserted into the uterine cavity releases 20μg of levonorgestrel daily over 5 years. In one case, the Lng-IUD was displaced. After 12 months, amenorrhea was described by 28% of women given the Lng-IUD and dysmenorrhea or spotting by another 50%; 22% of these women had normal menstrual flow. Dysmenorrhea continued at a moderate or severe level in 45% of women treated by surgery alone. The absolute risk reduction of recurrent dysmenorrhea in the Lng-IUD group was 35%. Dyspareunia and nonmenstrual pain also were less frequent in the IUD group. Tolerable side effects developed in 8 of 20 women assigned to receive the IUD. At follow-up, 75% of women in the Lng-IUD group and 50% of those in the surgery-only group were satisfied or very satisfied with their treatment. This pilot study suggests that, in women with symptomatic endometriosis, inserting a Lng-IUD after conservative laparoscopic surgery reduces the chance of recurrent dysmenorrhea and provides a high level of patient satisfaction, at least over the medium term.

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. Patient(s) 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.

Objective To ascertain whether adjuvant gonadotropin-releasing hormone (GnRH) agonist therapy decreases blood loss during abdominal myomectomy. Design Randomized controlled trial. Setting Academic reproductive surgery center. Patient(s) One hundred premenopausal women requiring first-line conservative surgery for symptomatic intramural or subserous fibroids. Intervention(s) Eight weeks of treatment with depot triptorelin before myomectomy or immediate surgery. Main outcome measure(s) Intraoperative blood loss, operating time, degree of difficulty of the procedure, and short-term rate of fibroid recurrence. Result(s) Mean (±SD) intraoperative blood loss was 265 ± 181 mL in triptorelin recipients and 296 ± 204 in patients who had immediate surgery (mean difference, −31 mL [95% CI, −108 to 46 mL]). No significant differences were observed in blood loss according to uterine volume, number of fibroids removed, or total length of myometrial incisions. Most procedures in either group were of routine difficulty. On ultrasonography 6 months after myomectomy, four women in the GnRH agonist group and one in the immediate surgery group had tumor recurrence. Conclusion(s) Treatment with a GnRH agonist before abdominal myomectomy has no significant effect on intraoperative blood loss. Thus, systematic use of medical therapy before abdominal myomectomy does not seem to be justified.

Objectives To evaluate the efficacy of veralipride, a benzamide derivative, in the treatment of hot flushes induced by GnRH agonists (GnRH-a) and to study peripheral blood mononuclear cell β -endorphin concentrations during drug administration. Design Randomized, placebo-controlled, double-blind trial. Setting Academic department of obstetrics and gynecology. Patients Forty women of mean age 43±5years who experienced disturbing hot flushes during a 4-month course of tryptorelin depot for myoma-associated menorrhagia. Interventions Treatment with oral veralipride 100mg/d (20 subjects) or matching placebo (20 subjects) during the third month of GnRH-a administration. Main Outcome Measures Modifications of frequency and severity of hot flushes as shown by a 0 to 6-point vasomotor scoring system and variations of β -endorphin levels in peripheral blood mononuclear cells. Results Two subjects in each group dropped out of the study. The median (range) vasomotor score at the end of the second month of treatment was 4 (3 to 6) in both the veralipride and placebo group. At the end of the third and fourth months the median (range) scores were, respectively, 2 (0 to 6) versus 4 (1 to 6) and 2 (0 to 5) versus 4 (1 to 6). No significant variations in mononuclear cell β -endorphin concentrations were recorded. Serum PRL levels rose from 11.7±5.7 to 132.3±65.0ng/mL (conversion factor to SI unit, 1.0) during veralipride administration and returned to 10.6±3.7ng/mL after drug withdrawal. Conclusion Veralipride reduced vasomotor symptoms induced by a GnRH-a. Transient hyperprolactinemia was the main side effect observed. The mode of action of the drug in GnRH-a–treated patients and possible interactions with endogenous opioid peptides need further elucidation.

To evaluate the efficacy of goserelin versus a low-dose cyclic oral contraceptive (OC) in improving pelvic pain in women with endometriosis and to compare recurrence of symptoms during follow-up.Open-label, randomized trial.University hospital endometriosis center.Fifty-seven women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis.Six-month treatment with goserelin depot (n = 29) or a low-dose cyclic OC (n = 28) followed by 6-month follow-up.Variation in severity of symptoms during treatment and at the end of follow-up as shown by a linear analog scale and a verbal rating scale.At 6 months of treatment, a significant reduction in deep dyspareunia was observed in both groups, with goserelin superior to the OC at linear analog scale assessment. Nonmenstrual pain was diminished on both scales without differences between treatments. Women taking the OC experienced a significant reduction in dysmenorrhea. At the end of follow-up, symptoms reappeared without differences in severity between the groups.Low-dose cyclic OCs may be a valuable alternative for the treatment of dysmenorrhea and nonmenstrual pain associated with endometriosis. Symptoms recurred in most subjects 6 months after drug withdrawal.Physicians at the University of Milan in Italy compared data on 29 endometrial patients who received 3.6 mg goserelin in a 28-day subcutaneous depot formulation for 6 months to treat nonmenstrual pelvic pain, dysmenorrhea, and pain during coitus (dyspareunia) with data on 28 other endometrial patients treated with a low-dose monophasic oral contraceptive (OC) (.02 mg ethinyl estradiol and 0.15 mg desogestrel) for 6 months. They followed the women for 6 months after treatment ended. The physicians wanted to determine the efficacy of goserelin, a gonadotropin-releasing hormone (GnRH) agonist, versus a low dose OC to relieve pelvic pain in patients with endometriosis and to compare pain recurrence after drug withdrawal. (GnRH agonists are current medical treatments for pelvic pain, but they have several side effects and are expensive; and therefore their use is restricted.) At the end of treatment, both goserelin and the low-dose OC significantly reduced dyspareunia (p .01), especially goserelin according to the linear analog scale (pain symptom score, 1.8 points lower). Both treatments improved nonmenstrual pain equally at the end of treatment (p .01). The low-dose OC reduced dysmenorrhea greatly at the end of treatment (p .01). The researchers could not evaluate dysmenorrhea in goserelin cases, since these patients experienced amenorrhea. The only persistent significant reduction at the end of follow-up occurred with dyspareunia in goserelin patients (p .05). In the other patients, pelvic pain returned to baseline levels 6 months after treatment ended. The severity of pelvic pain did not differ between groups 6 months after follow-up. These results suggested that low-dose OCs may be an effective alternative treatment for dysmenorrhea and nonmenstrual pelvic pain linked to endometriosis.

Objective To assess the use and effectiveness of IVF in a cohort of women undergoing surgery for endometriosis. Design Cohort study. Setting University hospital. Patient(s) Four hundred thirty-eight patients who attempted to become pregnant after conservative surgery for endometriosis. Intervention(s) Interview. Main Outcome Measure(s) Pregnancy and IVF use. Result(s) One hundred ninety-four women conceived in vivo (44%). One hundred twenty-four women did not undergo IVF despite their infertility status (51% of the group of women who failed to conceive in vivo). One hundred thirty-nine women underwent at least one IVF attempt. The cumulative rate of IVF use at 36 months of infertility was 33%. The live-birth/ongoing pregnancy rate per started cycle and per patient was 10% and 20%, respectively. Conclusion(s) In a large tertiary care and referral center, IVF played only a minor role in the treatment of endometriosis-associated infertility.

Objective To evaluate the efficacy, safety, and tolerability of an estrogen–progestogen combination versus low-dose norethindrone acetate in the treatment of persistent pain after surgery for symptomatic rectovaginal endometriosis. Design Randomized controlled trial. Setting Academic center. Patient(s) Ninety women with recurrent moderate or severe pelvic pain after unsuccessful conservative surgery for symptomatic rectovaginal endometriosis. Intervention(s) Twelve-month, continuous treatment with oral ethinyl E 2 , 0.01 mg, plus cyproterone acetate, 3 mg/day, or norethindrone acetate, 2.5 mg/day. Main Outcome Measure(s) Degree of satisfaction with therapy. Result(s) Seven women in the ethinyl E 2 plus cyproterone acetate arm and five in the norethindrone acetate arm withdrew because of side effects (n=5), treatment inefficacy (n=6), or loss to follow-up (n=1). At 12 months, dysmenorrhea, deep dyspareunia, nonmenstrual pelvic pain, and dyschezia scores were substantially reduced without major between-group differences. Both regimens induced minor unfavorable variations in the serum lipid profile. According to an intention-to-treat analysis, 28 (62%) out of 45 patients in the ethinyl E 2 plus cyproterone acetate group and 33 (73%) out of 45 in the norethindrone acetate group were satisfied with the treatment received. Conclusion(s) Low-dose norethindrone acetate could be considered an effective, tolerable, and inexpensive first-choice medical alternative to repeat surgery for treating symptomatic rectovaginal endometriotic lesions in patients who do not seek conception.

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.

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.

Objective: To determine whether the depth and volume of the pouch of Douglas differs in patients with endometriosis with and without deep lesions and to compare them with subjects with a healthy pelvis or with diseases other than endometriosis. Design: Prospective, comparative study. Setting: Tertiary care and referral center for patients with endometriosis. Patient(s): Women undergoing laparoscopy for infertility, pelvic pain, or adnexal anomalies (deep endometriotic rectovaginal lesions in 16 cases, endometriosis without deep lesions in 127 cases, miscellaneous anomalies in 35 cases, and normal pelvis in 26 cases). Intervention(s): Douglas pouch depth measurement from the upper border of uterosacral ligaments to its base with a calibrated probe and volume assessment by a fluid-filling technique. Main Outcome Measure(s): Douglas pouch depth and volume. Result(s): Mean (±SD) Douglas pouch depth and volume measurements were 3.6 ± 1.6 cm and 41.6 ± 19.3 mL in women with deep endometriosis, 5.3 ± 0.8 cm and 67.2 ± 18.1 mL in those with peritoneal and ovarian lesions only, 5.2 ± 0.9 cm and 67.6 ± 12.6 mL in those with miscellaneous conditions, and 5.5 ± 0.8 cm and 65.8 ± 10.9 mL in those with normal pelvis. Conclusion(s): Reduced Douglas pouch depth and volume in women with deep endometriosis suggest that such lesions develop not in the rectovaginal septum but intraperitoneally and that burial by anterior rectal wall adhesions creates a false bottom, giving an erroneous impression of extraperitoneal origin.

Objective: To evaluate the efficacy and safety of an intrauterine system releasing 20 μg of levonorgestrel per 24 hours in the long-term treatment of recurrent dysmenorrhea in women already operated on conservatively for endometriosis. Design: A prospective noncomparative pilot study. Setting: A tertiary care and referral academic center for patients with endometriosis. Patient(s): Twenty parous women with recurrent moderate or severe dysmenorrhea after conservative surgery for endometriosis who did not want further children. Intervention(s): A levonorgestrel-releasing intrauterine system was inserted in each woman within 7 days of the start of a menstrual cycle. Main Outcome Measure(s): Variations in severity of dysmenorrhea during treatment according to a 100-mm visual analogue scale and a 0–3-point verbal rating scale, modification of a pictorial blood-loss assessment chart devised to evaluate the amount of menstrual flow, and degree of satisfaction after 12 months of therapy. Result(s): One woman was lost to follow-up after achieving amenorrhea and expressing satisfaction, and 1 requested system removal because of weight gain and abdominal bloating. In another subject, the levonorgestrel intrauterine system was expelled 3 months after insertion. The menstrual patterns in the remaining 17 women were characterized by amenorrhea in 4 cases, hypomenorrhea or spotting in 8, and normal flow in 5. Baseline and 12-month follow-up mean ± SD blood loss scores were 111 ± 36 and 27 ± 26, respectively. At the same time, mean ± SD visual analogue and verbal rating scale scores dropped, respectively, from 76 ± 12 to 34 ± 23 points and from 2.5 ± 0.5 to 1.2 ± 0.5 points. Four women were very satisfied with treatment, 11 were satisfied, 2 were uncertain, and 3 were dissatisfied at 12-month follow-up. Conclusion(s): Because of the amenorrhea or hypomenorrhea induced in most women, a levonorgestrel intrauterine system greatly reduced menstrual pain associated with endometriosis and achieved a high degree of patient satisfaction.

Objective: To investigate the effectiveness of double IUI and to determine the optimal timing of IUI in relation to hCG administration. Design: Prospective randomized study. Setting: Infertility Center, Department of Obstetrics and Gynecology, University of Milan. Patient(s): Patients with male factor and unexplained infertility undergoing controlled ovarian hyperstimulation (COH) and IUI. Intervention(s): After COH with clomiphene citrate and gonadotropins, patients were randomly assigned to one of the following groups: group A received a single IUI 34 hours after hCG administration, group B received a double IUI 12 hours and 34 hours after hCG administration, and group C received a double IUI 34 hours and 60 hours after hCG administration. Main Outcome Measure(s): Number of follicles >15 mm in diameter on the day of hCG administration, number of motile spermatozoa inseminated, clinical pregnancy rate. Result(s): Two hundred seventy-three patients underwent 449 treatment cycles: 90 patients were treated for 156 cycles in group A, 92 patients for 144 cycles in group B, and 91 patients for 149 cycles in group C. The overall pregnancies rates for groups A, B, and C were 13 (14.4% per patient and 8.3% per cycle), 28 (30.4% per patient and 19.4% per cycle), and 10 (10.9% per patient and 6.7% per cycle), respectively. There was a statistically significant difference between group B and groups A and C. Conclusion(s): Our data indicate that two IUIs performed 12 hours and 34 hours after hCG administration is the most cost-effective regimen for women undergoing COH cycles with clomiphene citrate and gonadotropins. Although the second insemination adds up to a slightly higher cost, it significantly increases the chance of pregnancy.

To determine the effect of myomectomy as a therapy for infertility and to define the factors that influence reproductive outcome.Retrospective study of a case series.An academic department specializing in conservative surgery.A total of 138 infertile women who underwent first-line conservative surgical treatment at laparotomy for uterine leiomyomas over an 8-year period.Data were collected on baseline clinical characteristics, surgical details, and subsequent reproductive history.Cumulative pregnancy rates at 24 months according to selected clinical and fibroid characteristics.Pregnancy occurred in 76 women. The 24-month cumulative probability of conception according to the Kaplan-Meier method was 87% in patients30 years of age, 66% in patients 30-35 years of age, and 47% in patients35 years of age. The pregnancy rates in women with and without minor infertility factors in addition to myomas were 56% and 71%, respectively, and those in women with2 years versusor =2 years of infertility were 84% and 51%, respectively. The size and site of the largest myoma and the total number of tumors removed did not influence the outcome.Our results suggest a benefit of myomectomy in infertile patients. However, women should be counseled carefully before surgery because the determinants of outcome appear to be independent of treatment.

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% (3570; 95% CI, 37.8% to 62.2%). The overall crude conception rate after therapy among women who desired pregnancy was 44% (86194; 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.

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.