Retreatment with nafarelin for recurrent endometriosis symptoms: efficacy, safety, and bone mineral density.

OBJECTIVE: To assess the efficacy, safety, and effect on bone mineral density of a 3-month course of retreatment with intranasal nafarelin acetate for recurrent symptoms of endometriosis. DESIGN: Multicenter, open-label, nonrandomized clinical trial. SETTING: Eleven hospital-based and private practices. PATIENT(S): Thirty-six women with endometriosis symptoms recurring after 3 or 6 months of treatment with nafarelin. INTERVENTION(S): Nasal nafarelin 200 micrograms twice daily for 3 months. MAIN OUTCOME MEASURE(S): Assessments for dysmenorrhea, dyspareunia, pelvic pain, tenderness, and induration. Measurement of bone mineral density of the lumbar spine. RESULT(S): Improvements from admission to the end of retreatment were significant for dysmenorrhea, pelvic pain, tenderness, induration, and dyspareunia. Three months after retreatment ended, mean symptom scores for dysmenorrhea and pelvic tenderness, although worse than at the end of retreatment, were still significantly better than scores at admission. Mean bone mineral density 3 months after retreatment was 0.56% lower than before retreatment and 1.94% lower than before initial treatment. CONCLUSION(S): Three-month nafarelin retreatment for recurrent endometriosis symptoms was effective and safe.

Prediction of pregnancy in infertile women based on the American Society for Reproductive Medicine's revised classification of endometriosis.

OBJECTIVE: To estimate the empirical relationship between the revised American Society for Reproductive Medicine's classification of endometriosis and pregnancy rates after treatment. DESIGN: Retrospective analysis. PATIENT(S): Patients seen by four practicing physicians. INTERVENTION(S): Medical and/or surgical therapy for endometriosis. MAIN OUTCOME MEASURE(S): Pregnancy defined as ongoing or delivered. RESULT(S): There were no significant differences in pregnancy rates across stages of endometriosis. There was a slight decline in pregnancy rates among patients with Stage IV endometriosis, but statistical significance was not achieved. CONCLUSION(S): The use of an arbitrary weighted system for assigning scores to individual categories of disease, or for computing a total score, has limited the overall effectiveness of the classification system to predict pregnancy.

Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain.

OBJECTIVES: To determine the effectiveness of a 3-month course of nafarelin and, furthermore, to determine the long-term efficacy in patients treated for 3 and 6 months with nafarelin for symptoms associated with endometriosis. DESIGN: Double-blind, prospective, multicenter, clinical trial. SETTING: Fifteen reproductive endocrine clinics throughout the United States. PATIENTS: One hundred seventy-nine women with pelvic pain and endometriosis. INTERVENTIONS: Patients were assigned randomly to 3 months nafarelin followed by 3 months of placebo (n = 91) or to 6 months nafarelin (n = 88) in a prospective, randomized, double-blind multicenter trial. Patients were followed for 12 months after cessation of therapy. MAIN OUTCOME MEASURES: Patient-reported pain scores and physician-reported physical exam findings. RESULTS: Pain scores dropped significantly by the end of treatment in both groups. Symptoms recurred in both groups, and pain scores gradually increased during the follow-up period but always remained below baseline in both groups. No significant difference in efficacy was noted between the groups. A total of 26% of patients in each group underwent retreatment for recurrent symptoms. CONCLUSIONS: A 3-month course of nafarelin provided effective symptom relief for endometriosis. One year follow-up demonstrated continued pain relief but with gradual return of symptoms.

Nafarelin therapy in endometriosis: long-term effects on bone mineral density.

OBJECTIVE: The study intent was to examine long-term effects on bone mass of 3 or 6 months of nafarelin therapy for endometriosis. STUDY DESIGN: Women with established endometriosis (N = 173) were randomized to receive nafarelin (200 micrograms intranasally twice a day) for either 3 or 6 months in a double-blind fashion. Bone mineral density was measured by dual energy x-ray absorptiometry at lumbar spine and proximal femoral sites for 18 months. RESULTS: Bone mineral density declined at spinal and femoral sites similarly in both 3- and 6-month treatment groups. There was a partial, but incomplete, return to baseline levels after 12 to 15 months of follow-up. The recovery of bone mass was more complete in subjects with higher dietary calcium intakes. CONCLUSION: Nafarelin therapy for endometriosis results in a sustained loss of spinal and femoral bone density, particularly in women with lower calcium intakes.

Presence of Chlamydia, Mycoplasma, ureaplasma, and other bacteria in the upper and lower genital tracts of fertile and infertile populations.

OBJECTIVE: The genital mycoplasmas (Mycoplasma hominis and Ureaplasma urealyticum) and Chlamydia trachomatis have been implicated as possible etiologic factors in infertility. Their role in patients with infertility needs to be further defined. METHODS: Seventy-nine infertile patients underwent laparoscopy with cultures obtained for aerobic and anaerobic bacteria, Chlamydia, Mycoplasma, and Ureaplasma from the peritoneal fluid, fallopian tube, endometrium, and endocervix. Cultures for similar organisms were taken from the endocervix of 80 fertile women in their first trimester. Culture results were also compared according to ovulatory status and laparoscopic findings in the infertile group. RESULTS: There were no differences in the recovery of Ureaplasma (29% vs. 28%) or Chlamydia (4% vs. 0%) positive cervical cultures in the fertile and infertile groups, respectively. However, a significantly higher number of Mycoplasma positive cervical cultures (14% vs. 5%, P = 0.05) were found in the fertile group. Only two upper genital tract cultures were found to be positive (Ureaplasma). CONCLUSIONS: Therefore, if these organisms play a role in infertility, they are present and eradicated prior to infertility work-up and thus do not supports the use of a routine trial of antibiotics prior to laparoscopy.

Tubal pregnancy with normal hysterosalpingogram and negative serum pregnancy test.

A patient undergoing evaluation for primary infertility with regular menses had a normal hysterosalpingogram in the follicular phase and underwent diagnostic laparoscopy the next day, with the finding of a tubal pregnancy. The patient had a negative serum pregnancy test. Although a normal hysterosalpingogram and negative serum pregnancy test are each rare with a tubal pregnancy, the combination of the two occurring in a tubal pregnancy is previously unreported and did not exclude the diagnosis in this case.

Use of danazol in conservative surgery.

Any type of injury, inflammation or noninfectious condition can cause an adhesion. Among noninfectious conditions that cause adhesions, endometriosis is the most common. a six-month preoperative regimen of Danocrine (danazol) resulted in a reduction in pelvic vascularity and inflammation, theoretically reducing the risk of postoperative adhesions. The preoperative use of danazol also makes laparoscopic surgery possible for more patients.

Recombinant tissue plasminogen activator reduces adhesion formation in a rabbit uterine horn model.

To evaluate the potential benefit of recombinant tissue plasminogen activator (rt-PA) as an agent for reducing postoperative adhesions, a rabbit uterine horn model was studied. Fifty-five rabbits underwent laparotomy, at which time the uterus was abraded with scalpel and a thermal injury was induced with electrocautery. Before abdominal closure, rt-PA was applied topically in various dosages. Adhesions were evaluated at a second laparotomy performed 2 weeks later. Treatment significantly reduced both adhesion quantity (P less than 0.001) and adhesion density (P less than 0.001). In the second phase of the study, the efficacy of rt-PA as an adjunct to surgical adhesiolysis was investigated. Again, a dose-related treatment effect was observed (P less than 0.001). No wound healing or bleeding complications were seen.

Classification of endometriosis.

The classification of endometriosis has evolved during this century under the influence of many factors. Although classifications initially paralleled the staging of pelvic malignancies, more modern systems follow the natural progression of this pathologic process. The diagnosis of endometriosis at earlier stages has been limited by the technology of the era. Previously, only patients with more severe disease or symptoms were evaluated and treated. Earlier therapies were more radical and centered on pain relief achieved with removal of the internal genitalia. The objectives of classification were to provide standardized documentation of the disease and--it was hoped--define those patients amenable to less radical therapy. As our diagnostic and therapeutic capabilities grew, so did our interest in infertile women with endometriosis and the treatment of such patients. The diagnosis of endometriosis was often made at an earlier stage of involvement, and therapy stressed repair rather than removal. Description of pelvic involvement, has become more detailed and accurate, and the stage of disease has become prognostic of future fertility. The basic tenet of the R-AFS classification system is to provide an objective and universal method for describing the severity of disease visualized at laparotomy or laparoscopy. Stage of disease will aid the physician in choosing the therapy most suited for the individual patient. If reparative surgery is undertaken, the stage of disease will reflect the extent of pelvic reconstruction required. Quantifying disease severity will, it is hoped, make it predictive of success in conception and prognostic of the need for future medical or surgical treatment. It will also serve to stratify patients with a similar degree and distribution of disease into somewhat homogeneous groups. This will permit reasonable comparisons of effectiveness of different therapies and investigators' methods. Refinement of this type of classification scheme will depend on critical analysis of the system's prognostic capabilities. Further studies will help elucidate the relative importance of individual variables on the potential for success in achieving pregnancy.

Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial.

Treatment with nafarelin, a gonadotropin-releasing hormone agonist, reversibly inhibits ovarian function and induces hypoestrogenemia. To determine the efficacy of such hormonal manipulation in the treatment of endometriosis, we randomly assigned 213 patients with laparoscopically confirmed endometriosis to receive, for six months, either nafarelin by nasal spray (400 or 800 micrograms per day) or oral danazol (800 mg per day). Placebo nasal spray and placebo tablets were used to double blind the study. Pretreatment and post-treatment laparoscopies were compared by means of the American Fertility Society's scoring system. More than 80 percent of the patients in each treatment group had a reduction in the extent of disease as assessed by laparoscopy. The mean laparoscopic scores decreased from 21.9 to 12.6 with 800 micrograms of nafarelin, from 20.4 to 11.7 with 400 micrograms of nafarelin, and from 18.4 to 10.5 with danazol (P = 0.0001 within each group; there were no statistically significant differences between the groups). The percentage of women with severely painful symptoms of endometriosis decreased from about 40 percent to 5 to 10 percent, whereas the percentage with no or minimal discomfort rose from 25 to 70 percent. Of the 149 patients who tried to become pregnant, 58 (39 percent) succeeded after the completion of treatment; similar rates of pregnancy applied to the three treatment groups. Danazol use decreased high-density lipoprotein levels and increased low-density lipoprotein levels. These changes were not observed in nafarelin users, but a higher percentage of them reported hot flashes and decreased libido. We conclude that nafarelin is an effective agent for treating endometriosis and has few side effects other than hypoestrogenism.

Linear regression analysis of ultrasound follicular growth series: evidence for an abnormality of follicular growth in endometriosis patients.

Follicular diameter growth is a highly linear function of time. Recently, the potential utility of linear regression-derived parameters for describing and comparing cycles of follicular growth was described. The linearity of growth, growth rate constant (K), calculated date of growth onset (Do), total growth period (TGP), menstrual age at apparent ovulation (MAov), and peak follicular diameter (PFD) have been calculated from the follicular growth series of a group of patients with laparoscopically diagnosed endometriosis (n = 46). These parameters were compared with those of a group of normal volunteers (n = 18). The authors found significant differences between endometriosis patients and controls in follicular growth rate and total growth period. The effect of patients' clomiphene citrate usage on growth parameters in these patients was examined. Abnormalities in interrelationships between the growth parameters were detected, suggesting the possibility of subtle defects in the regulation of follicular growth in these patients.

Serum and peritoneal fluid proteins in women with and without endometriosis.

We examined the proteins in serum and peritoneal fluid of women with endometriosis (and of healthy controls) for evidence of an autoimmune response that might account for their impaired fertility. No antibodies against endometrial glycoproteins or against "progestin dependent endometrial protein" (PEP) were found in any serum or peritoneal fluid sample. Levels of PEP were not different in serum from women with moderate to severe endometriosis (n = 6), with mild endometriosis (n = 21), or from disease-free cycling controls (n = 19). PEP levels in peritoneal fluid from mild endometriosis and from controls did not differ but were elevated ten times in fluid obtained in the secretory phase from women with moderate to severe disease. This suggests that PEP levels in peritoneal fluid reflect the extent of ectopic endometrial growth. The salient finding was a heretofore undescribed protein (mol wt 70,000) in secretory phase peritoneal fluid samples (18/20) and its absence during the proliferative phase (0/35).

Peritoneal fluid plasminogen activator activity in endometriosis and pelvic adhesive disease.

Plasminogen activator activity in PF was assayed by the fibrinolysis method described by Strickland and Beers. In 45 patients studied, there were no discernible differences according to whether patients had endometriosis and/or pelvic adhesive disease. No differences were detected according to when in the menstrual cycle the sample of PF was obtained. These data are in concordance with a previous report and taken together suggest that there is no difference in fibrinolytic mechanisms in PF in patients with or without endometriosis and/or pelvic adhesive disease, when compared with control subjects. If such differences exist, they may be present in the tissues, per se, but are not discernible in PF.