James M. Wheeler

Role of Endometrial Suppression on the Frequency of Intrauterine Adhesions after Resectoscopic Surgery

STUDY OBJECTIVES To evaluate long-term effects of operative hysteroscopy on the development of intrauterine adhesions (IUA), and to determine whether hypoestrogenism has a modulatory role in preventing IUA. DESIGN Prospective, randomized study (Canadian Task Force classification I). SETTING Tertiary-care teaching hospital. PATIENTS Ninety-five women requiring resectoscopic surgery. Intervention. Hysteroscopic surgery using the resectoscope and 1.5% glycine for uterine distention. MEASUREMENTS AND MAIN RESULTS Indications for hysteroscopy were polyps (28 patients), solitary myoma (32), multiple myomata (20), and uterine septa (15). Patients in each group were randomized to endometrial suppression with danazol or placebo. Second-look office hysteroscopy with CO2 for uterine distention was performed after the first menses after surgery to assess the frequency, extent, and severity of IUA. The likelihood and severity of IUA depended on the pathology treated at initial surgery. Of women treated for polyps and uterine septa, in only one with septa (placebo group) developed IUA. Mild IUA formation was present in 10 patients (31.3%) with solitary fibroids and 9 (45.5%) with multiple myomata. The frequency was similar in placebo- and danazol-treated groups with both solitary and multiple myomas (50% and 44.4% vs 50% and 55.6%). All IUA were lysed during second-look surgery, except in one woman with multiple myomata who required repeat resectoscopy. CONCLUSION Intrauterine adhesions are the major long-term complication of operative hysteroscopy, with frequency dependent on the pathology initially treated. Second-look office hysteroscopy is a cost-effective method of diagnosing and lysing IUA after resectoscopy.

Recurrent endometriosis: Incidence, management, and prognosis☆

The rate of recurrence of endometriosis after treatment has varied from 2% to 47% in published reports. In order to determine whether a meaningful prognosis for recurrence can be rendered, 423 patients treated with conservative surgical procedures from 1967 to 1982 were followed as outpatients. From among these, 62 patients underwent reoperation. Annual rates of recurrence based on findings at reoperation ranged from 0.9% in the first postoperative year to 13.6% in the eighth postoperative year. The cumulative 3- and 5-year recurrence rates were 13.5% and 40.3%, respectively. Severity of disease was not predictive of recurrence. Pregnancy did not preclude, but did delay, recurrence. Forty-seven percent of infertile patients with recurrent endometriosis conceived after a second conservative operation. Of 20 patients who had a second conservative operation for endometriosis, 20% required a third laparotomy. This is the first study of postoperative recurrent endometriosis to utilize a control group and the first to report annual rates of recurrence and reoperation.

Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis

OBJECTIVE We aimed to assess the efficacy of depot leuprolide versus danazol in the treatment of endometriosis. STUDY DESIGN A double-blind randomized trial of 270 patients from 22 centers compared the pretreatment and posttreatment laparoscopic extent of endometriosis. Pretreatment and posttreatment endometriosis symptoms and signs were assessed with standardized methods. RESULTS When compared with danazol, leuprolide depot caused a more rapid and profound suppression of estradiol. Leuprolide depot and danazol were similarly efficacious in decreasing the extent of endometriosis, as well as the pain and tenderness associated with endometriosis. CONCLUSION Depot leuprolide is an effective alternative to danazol in decreasing the extent of endometriosis and endometriosis-related pain.

The use of an amniotic membrane graft to prevent postoperative adhesions.

Grafts of trypsin-treated, gamma-irradiated human amniotic membranes were used to cover injured uterine horns of nulliparous female rabbits to prevent adhesions. In this study, the gradual integration of the membranes into the serosal layer of the uterus, together with marked neovascularization, was observed. By the 30th postoperative day, the grafts had been completely integrated, with little evidence of rejection and no evidence of infection at the graft sites. Of 30 uterine horns treated with membrane grafts, only 4 (13.4%) showed any adhesion formation at or among the graft sites. All of the 24 untreated controls showed adhesion formation at the site of injury. Furthermore, whatever adhesions were found in membrane-treated horns could be graded as thin and filmy, accounting for less than 10% of the surface area of the graft, whereas the controls showed dense, thick adhesions covering 50% to 100% of the injured areas. We conclude that these specially prepared amniotic membranes are safe and effective in dramatically reducing postoperative adhesion formation in this animal model.

The effects of duration of CO2 insufflation and irrigation on peritoneal microcirculation assessed by free radical scavengers and total glutathion levels during operative laparoscopy.

STUDY OBJECTIVE To investigate the effects of peritoneal exposure to carbon dioxide (CO2) on peritoneal microcirculation and free radical scavenger (FRS) metabolism, and its role in potential adhesion formation after operative laparoscopy. DESIGN Randomized, controlled study (Canadian Task Force classification I). SETTING University-affiliated hospital. PATIENTS Twenty-eight women undergoing operative laparoscopy for adnexal masses. INTERVENTION For each patient, a 1 x 1-cm sidewall peritoneal flap was excised at the end of laparoscopy and numbered randomly. Similar flaps obtained from 24 women immediately after entering the abdomen during laparotomy served as controls. MEASUREMENTS AND MAIN RESULTS Changes in glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were studied in homogenized peritoneal tissues. The duration of CO2 exposure and amount of CO2 used were correlated with levels of free radical scavengers and compared with controls. Mean CO2 exposure, amount of CO2 used, and CO2 pressure (15 mm Hg) was similar between low irrigation and irrigated laparoscopy (118.3 +/- 25 and 39.2 +/- 8.81 min and 125 +/- 20 and 44.5 +/- 6.81 min, respectively). The change in FRS levels was significantly correlated with duration and amount of CO2 exposure (r = -0.92). Levels of GSH-Px, SOD, CAT, and GSH were significantly lower in the CO2 exposure group than in controls (0.57 micro mol, 1.8 ng, 48.5 micro mol, 1.5 nmol vs 0.8 micro mol, 2.6 +/- 0.4 ng, 79 micro mol, 3.6 nmol, respectively). CONCLUSION Exposure to CO2 has adverse effects on peritoneal microcirculation and cell-protective systems, which are proposed mechanisms in adhesion formation. Avoiding long CO2 exposure and copiously irrigating the abdominal cavity throughout surgery may lessen these effects. The potential role of the peritoneal FRS system on postoperative adhesion formation and its relation to estrogen status mandates further studies.

Depot leuprolide acetate versus danazol in the treatment of women with symptomatic endometriosis: A multicenter, double-blind randomized clinical trial: II. Assessment of safety

OBJECTIVES This is the first multicenter, double-blind randomized clinical trial that compares a depot gonadotropin-releasing hormone agonist with danazol in the treatment of endometriosis. Efficacy results have been previously reported; this report focuses on safety data. STUDY DESIGN A total of 270 patients from 22 centers were randomly selected to receive either leuprolide acetate depot (3.75 mg injected monthly) or danazol (800 mg administered orally daily). Safety outcomes included adverse effects, clinical laboratory changes, and bone mineral density changes. RESULTS Most patients receiving either drug reported side effects, most of which were related to the hypoestrogenism of leuprolide (e.g., vasodilatation) and relative hyperandrogenism of danazol (e.g., weight gain). Similarly small numbers of patients dropped out of the two treatment groups because of the side effects encountered. Leuprolide depot caused a greater decrease in bone density; preliminary data suggest a return to baseline on cessation of the drug. Danazol was associated with alteration of serum lipids, specifically a significant decrease in high-density lipoprotein. CONCLUSIONS Although side effects were commonly reported in both groups, the drugs were similarly safe in terms of the absence of serious complications and the results of cessation of therapy. Side effects were largely reversible on discontinuation of medication. More longitudinal data are necessary before the possibility of long-term risks can be excluded, especially as they pertain to bone mineral density and lipids.

Adhesion formation after microlaparoscopic and laparoscopic ovarian coagulation for polycystic ovary disease

STUDY OBJECTIVE To compare the effects of microlaparoscopy and decreased CO2 exposure on peritoneal microcirculation and potential adhesion formation after ovarian surgery with those of conventional operative laparoscopy. DESIGN Prospective, randomized study (Canadian Task Force classification I). SETTING Teaching hospital. PATIENTS Eighteen women with polycystic ovary disease. INTERVENTIONS Microlaparoscopic or laparoscopic ovarian coagulation of the ovaries. MEASUREMENTS AND MAIN RESULTS Approximately 10 to 12 coagulation points were applied to each ovary. Two to 3 weeks after the initial surgery second-look microlaparoscopy was performed to determine the extent of adhesions in both groups. The frequency of adhesion formation and changes in glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were studied in homogenized peritoneal tissues obtained during surgery in each group. RESULTS Clinical profiles were similar between groups. Mean exposure, amount, and pressure of CO2 were significantly less in the microlaparoscopy group (p <0.05). The laparoscopy group had significantly more adhesions than the microlaproscopy group (24% vs 48%, p <0.05). The GSH-Px, SOD, CAT, and GSH levels were significantly lower in the laparoscopy group (0. 425 micromol, 1.2 ng, 37.55 micromol, and 0.9 nmol vs 0.755 micromol, 2.l ng, 625 micromol, and 2.6 nmol, respectively). CONCLUSION Reduced exposure to and amount of CO2 during microlaparoscopy may result in decreased adhesion formation compared with conventional laparoscopy. This effect may possibly be due to lack of or minimal adverse effects on peritoneal microcirculation and cell-protective systems, which are proposed mechanisms for adhesion formation and closely related to peritoneal injury. In addition, microlaparoscopy may be a cost-effective alternative to conventional laparoscopy. (J Am Assoc Gynecol Laparosc 6(2):159-163, 1999)

Postoperative danazol therapy in infertility patients with severe endometriosis

The value of perioperative medical therapy in the management of infertility patients with severe endometriosis is uncertain. Previous reports of pre- or postlaparatomy danazol provide no clear direction regarding efficacy. Of 200 consecutive cases of severe endometriosis, 138 infertility patients were selected for study. One hundred nineteen patients, the control group, had laparotomy alone; 19 had laparotomy followed immediately by danazol therapy. The pregnancy rate in the control group was 30% (36/119) versus 79% (15/19) in the study group, (P less than 0.001). The results of this preliminary report indicate that danazol treatment in the immediate postlaparotomy period of patients with severe endometriosis significantly improves the pregnancy rate over comparable patients treated with surgery alone. It is hoped that these results will encourage other surgeons to implement a prospective surgical-medical approach, so that the most efficacious treatment for infertile patients with severe endometriosis can be determined.

The degree of fluid absorption during hysteroscopic surgery in patients pretreated with goserelin

STUDY OBJECTIVE To assess the effects of pretreatment with the gonadotropin-releasing hormone analog goserelin on fluid absorption in patients undergoing hysteroscopic endometrial ablation. DESIGN Prospective, randomized, placebo-controlled study. SETTING A university-based clinic. PATIENTS Thirteen women with dysfunctional uterine bleeding who were scheduled for electrosurgical hysteroscopic ablation. INTERVENTIONS Seven women were randomized to receive luteal phase goserelin 3.75 mg and six saline in the menstrual cycle approximately 10 weeks before surgery. Operative hysteroscopy was carried out with glycine 1.5% mixed with 2% alcohol medium under constant pressure as an irrigant. The amount of irrigant used, irrigant deficit, blood levels of albumin and ethanol, hematocrit, hemoglobin, changes in sodium levels, and central venous pressure were compared between the groups. MEASUREMENTS AND MAIN RESULTS All of the patients had an unsuccessful course of medical therapy for at least 3 months and a normal endometrial biopsy. The age, weight, and uterine size were similar between the groups. The mean volume of irrigant used and operating time were similar in both groups (4.18 +/- 0.2 vs 4.5 +/- 0.5 L, and 33.7 +/- 1.5 vs 37 +/- 2.1 min). Although operating time, volume deficit, decrease in protein level, and hematocrit were less in the goserelin than in the saline group, the differences were not statistically significant (p >0.05). The ethanol levels in blood, decrease in Na+, and irrigant deficit were significantly lower in the goserelin than in the saline group (17.4 +/- 3.8 vs 25.3 +/- 4.2 mg/ml, 6.7 +/- 1.2 vs 9.1 +/- 0.9 mEq/L, and 0.49 +/- 0.08 vs 0.66 +/- 0.05 L, respectively; p <0.05). CONCLUSION Based on these results we conclude that in women undergoing hysteroscopic endometrial ablation, pretreatment with goserelin may decrease the absorption of hysteroscopic medium, prevent fluid overload, and improve the outcome possibly by causing hypovascularity and decreased endometrial growth.

Endometrial Na+, K+-ATPase pump function and vasopressin levels during hysteroscopic surgery in patients pretreated with GnRH agonist *

STUDY OBJECTIVE To investigate the effects of gonadotropin-releasing hormone (GnRH) analog pretreatment on endometrial Na+, K+-adenosine triphosphatase (ATPase) pump function and peripheral blood vasopressin levels, and their role in fluid absorption and mechanisms of hyponatremia in patients undergoing hysteroscopic endometrial ablation. DESIGN Prospective, randomized, placebo-controlled study (Canadian Task Force classification I). SETTING University-affiliated hospital. PATIENTS Seventeen women with dysfunctional uterine bleeding. INTERVENTION Nine women received a GnRH analog and eight received saline approximately 6 to 8 weeks before hysteroscopic ablation by electrosurgery. MEASUREMENTS AND MAIN RESULTS Both before randomization and immediately before surgery, endometrial biopsy samples were obtained and numbered consecutively without patient identification. Operative hysteroscopy was performed with glycine 1.5% mixed with 2% alcohol. The amount of irrigant and irrigant deficit; blood levels of albumin and ethanol; hematocrit and hemoglobin; changes in sodium levels; and central venous pressure were compared. The Na+, K+-ATPase pump activity was significantly increased in the GnRH analog group compared with the saline group and correlated with decreased estradiol levels (0.4 +/- 0.08 vs 0.26 +/- 0.06 micro mol/min/ml). Vasopressin levels were significantly lower in the GnRH group (3.2 +/- 0.9 vs 7.6 +/- 1.7 micro mol/L). Mean volume of irrigant used and operating time were similar in both groups. Volume deficit, decrease in protein, and hematocrit were less in GnRH than in the saline group. Blood ethanol levels, decrease in sodium, and irrigant deficit were significantly lower in GnRH group. CONCLUSION Pretreatment with GnRH analogs may prevent the adverse effects of estradiol on endometrial Na+, K+-ATPase and creates a protective mechanism against iatrogenic hyponatremia, which is more critical in women than men in case of absorption of irrigating fluid. Moreover, created hypoestrogenism may enhance Na+, K+-ATPase activity in brain as well as endometrium, thus decreasing womens susceptibility to hyponatremic complications and brain damage. Suppressed vasopressin levels may be protective against fluid absorption in GnRH analog-treated patients.