Decreased efficacy of twice-weekly intravaginal dehydroepiandrosterone on vulvovaginal atrophy.

OBJECTIVE: While daily intravaginal administration of 0.50% (6.5 mg) dehydroepiandrosterone (DHEA, prasterone) for 12 weeks has shown clinically and statistically significant effects on moderate to severe (MS) dyspareunia as the most bothersome symptom (MBS), the present study analyzes the effect of a reduced dosing regimen on MBS vaginal dryness. METHOD: Daily intravaginal 0.50% prasterone for 2 weeks followed by twice weekly for 10 weeks versus placebo. RESULTS: Maximal beneficial changes in vaginal parabasal and superficial cells and pH were observed at 2 weeks as observed for intravaginal 10 µg estradiol (E2). This was followed by a decrease or lack of efficacy improvement after switching to twice-weekly dosing. The decrease in percentage of parabasal cells, increase in percentage of superficial cells and decrease in vaginal pH were all highly significant (p < 0.0001 to 0.0002 over placebo) at 12 weeks. In parallel, the statistical significance over placebo (p value) on MBS vaginal dryness at 6 weeks was 0.09 followed by an increase to 0.198 at 12 weeks. For MBS dyspareunia, the p value of 0.008 at 6 weeks was followed by a p value of 0.077 at 12 weeks, thus illustrating a decrease of efficacy at the lower dosing regimen. The improvements of vaginal secretions, color, epithelial integrity and epithelial surface thickness were observed at a p value < 0.01 or 0.05 over placebo at 2 weeks, with a similar or loss of statistical difference compared to placebo at later time intervals. No significant adverse event was observed. Vaginal discharge related to the melting of Witepsol was reported in 1.8% of subjects. CONCLUSION: The present data show that daily dosing with 0.50% DHEA for 2 weeks followed by twice-weekly dosing is a suboptimal treatment of the symptoms/signs of vulvovaginal atrophy resulting from a substantial loss of the efficacy achieved at daily dosing.

Thermal balloon and rollerball ablation to treat menorrhagia: two-year results of a multicenter, prospective, randomized, clinical trial.

STUDY OBJECTIVE: To evaluate 2-year follow-up results in patients participating in a randomized, clinical trial comparing uterine balloon therapy with rollerball endometrial ablation. STUDY DESIGN: Prospective, randomized, clinical trial (Canadian Task Force classification I). SETTING: Fourteen university-affiliated and private practice sites. PATIENTS: Two hundred fifty-five women with menorrhagia. INTERVENTIONS: Patients were randomized to rollerball or uterine balloon endometrial ablation. MEASUREMENTS AND MAIN RESULTS: Patient satisfaction with both treatments was consistently high. Only 15 hysterectomies had been performed (6 for menorrhagia) at the end of 2 years, 11 in the rollerball group, 4 in the balloon therapy group. CONCLUSION: Endometrial ablation by both procedures was highly successful in avoiding hysterectomy and relieving symptoms of menorrhagia. Additional benefits were reduction in dysmenorrhea and premenstrual syndrome.

Value of estradiol response after human chorionic gonadotropin administration in predicting in vitro fertilization success.

OBJECTIVE: To determine whether the serum E2 response after the administration of exogenous hCG is predictive of outcome during IVF. DESIGN: Prospective, noncomparative cohort. SETTING: Two academic centers and one private-practice IVF program. PATIENT(S): Two hundred twenty-two couples undergoing IVF for infertility arising from ovarian dysfunction, asthenoteratospermia, endometriosis, tubal disease, or unexplained infertility. MAIN OUTCOME MEASURE(S): Implantation, pregnancy, and miscarriage rates were compared in cycles that demonstrated an increase, decrease, or plateau in the serum E2 level on the day after hCG administration. The effects of age, cause of infertility, and maximum E2 value on outcome were evaluated. RESULT(S): Ninety-two cycles resulted in a clinical pregnancy and 130 cycles failed. Of 115 cycles in which the E2 level rose, 42 (37%) resulted in an ongoing pregnancy; among cycles with plateauing E2 responses, 20 of 69 (29%) resulted in a pregnancy. Fifteen of 38 (39%) of cycles exhibiting a drop in serum E2 resulted in an ongoing pregnancy. No statistically significant differences in ongoing pregnancy rates were noted in the increasing, plateauing, or decreasing E2 response groups. CONCLUSION(S): E2 values obtained on the day after hCG administration are not predictive of outcome in women undergoing IVF.

Measurement of serosal temperatures and depth of thermal injury generated by thermal balloon endometrial ablation in ex vivo and in vivo models.

OBJECTIVE: To evaluate the safety profile of endometrial ablation performed with a thermal balloon as defined by serosal temperature elevation and depth of injury. DESIGN: Observational study with histopathologic correlation conducted in ex vivo and in vivo phases. SETTING: Academic medical center. PATIENT(S): Twenty patients undergoing total abdominal hysterectomy. INTERVENTION(S): Endometrial ablation with a thermal balloon. MAIN OUTCOME MEASURE(S): Serosal temperature elevation and histologic depth of injury. RESULT(S): Ex vivo phase results revealed serosal temperatures remained within a safe physiologic range (<45 degrees C). Greatest depth of myometrial injury in the premenopausal uteri was 5.8 mm over the anterior lower uterine segment. In postmenopausal uterus. the greatest depth of myometrial injury was 3.8 mm in the anterior midline. In vivo phase results revealed mean (+/- SD) peak serosal temperatures of 36.1 +/- 1.6 degrees C. As with the ex vivo phase. histologic examination revealed deep endometrial and superficial myometrial damage to all areas. The greatest depth of myometrial injury occurred in the midfundus at 3.4 mm. CONCLUSION(S): No patients experienced complications or adverse events secondary to treatment. Results showed that transuterine thermal injury is a highly unlikely scenario. In both phases of this study, histologic examination revealed that temperatures exposed to the endometrial layer were sufficient to cause tissue damage.

Thermal balloon and rollerball ablation to treat menorrhagia: a multicenter comparison.

OBJECTIVE: To compare the clinical efficacy and safety of a thermal uterine balloon system with hysteroscopic rollerball ablation in the treatment of dysfunctional uterine bleeding. METHODS: Two hundred fifty-five premenopausal women were treated in a randomized multicenter study comparing thermal uterine balloon therapy with hysteroscopic rollerball ablation for the treatment of menorrhagia. Preprocedural and postprocedural menstrual diary scores and quality-of-life questionnaires were obtained. Twelve-month follow-up data are presented on 239 women. RESULTS: Twelve-month results indicated that both techniques significantly reduced menstrual blood flow with no clinically significant difference between the two groups as reflected by return to normal bleeding or less (balloon 80.2% and rollerball ablation 84.3%). Multiple quality-of-life questionnaire results were also similar, including percent of patients highly satisfied with their results (balloon 85.6% compared with rollerball 86.7%). A 90% decrease in diary scores was seen in more than 60% of patients in both groups. Procedural time was reduced significantly in the uterine balloon therapy group. Intraoperative complications occurred in 3.2% of the hysteroscopic rollerball patients, whereas no intraoperative complications occurred in the thermal balloon group. CONCLUSION: In the treatment of dysfunctional uterine bleeding, uterine balloon therapy is as efficacious as hysteroscopic rollerball ablation and may be safer.

Laparoscopic management of ectopic pregnancy.

Management of ectopic pregnancy includes a high index of suspicion coupled with established algorithms of diagnosis using serum beta-human chorionic gonadotropin and transvaginal ultrasound. Early diagnosis and intervention usually leads to conservation of the involved tube. Careful follow up for persistent ectopic pregnancy leads to appropriate medical or surgical management. The use of methotrexate, either systemically or by local injection, may provide an alternative to surgery in selected patients with ectopic pregnancy.

Reproductive potential after treatment for persistent ectopic pregnancy.

We examined the success rate and reproductive outcome of 50 patients who had been treated for persistent EP after initial unsuccessful salpingostomy. All who underwent salpingectomy had successful treatment of their persistent EP. One treatment failure occurred after MTX. Of 50 women, 32 (61.5%) attempted conception after treatment for persistent EP. The cumulative clinical pregnancy rate after treatment for persistent EP was 59% at 36 months. There was a significant association between clinical pregnancy rate after persistent EP and those with normal contralateral fallopian tubes (P < 0.005). The relative risk of having a clinical pregnancy among those who attempted conception was 2.3 for those having a normal contralateral fallopian tube compared with those with a contralateral fallopian tube with obvious pathology. Intrauterine pregnancy rates after treatment of persistent EP were similar to those reported for primary treatment of EP.

Counter-regulatory response to hypoglycemia in the follicular and luteal phases of the menstrual cycle.

OBJECTIVE: To assess whether the phase of the menstrual cycle influences the counter-regulatory response to hypoglycemia. DESIGN: Prospective randomized euglycemia-hypoglycemia clamp studies in the follicular and luteal phases of the menstrual cycle in the same woman. SETTINGS: Clinical Research Center, Yale University School of Medicine. PATIENTS: Eight regularly menstruating nonobese women. MAIN OUTCOME MEASURES: Counter-regulatory hormonal response to hypoglycemia-epinephrine, norepinephrine, glucagon, cortisol, GH, and PRL; glucose homeostasis: rates of whole-body glucose appearance and utilization, and the rate of hepatic glucose production. RESULTS: In the follicular and luteal phases of the cycle fasting glucose levels (88 +/- 1 and 85 +/- 2 mg/dL, mean +/- SEM, respectively; conversion factor to SI units, 0.05551), basal glucose turnover (2.37 +/- 0.20 and 2.63 +/- 0.13 mg/kg per minute), basal insulin levels (10 +/- 1 and 9 +/- 1 microU/mL; conversion factor to SI units, 6.0), and insulin levels during the clamp study (53 +/- 3 and 45 +/- 4 microU/mL) were not significantly different. During the euglycemic phase of both studies, glucose utilization rose twofold (to 4.73 +/- 0.31 and 4.39 +/- 0.31 mg/kg per minute): hepatic glucose production was suppressed; and counter-regulatory hormones remained unchanged. Induction of hypoglycemia produced increases in the concentrations of counter-regulatory hormones that were indistinguishable in both phases of the cycle. Similarly, the increase in hepatic glucose production provoked during hypoglycemia was similar in each phase of the cycle (1.20 +/- 0.24 and 1.28 +/- 0.36 mg/kg per minute). CONCLUSION: The counter-regulatory hormonal response to hypoglycemia, as well as the metabolic sequelae of these hormonal changes, are similar in the follicular and luteal phases of the menstrual cycle.

Diagnosing proximal tubal obstruction: evaluation of peak intrauterine pressures using four common cannula techniques in extirpated uteri.

OBJECTIVE: To compare the ability of four chromotubation techniques to generate and maintain intrauterine pressures in the diagnosis of proximal tubal obstruction. METHODS: Sixteen extirpated uteri were used for this study. A pressure catheter was placed through the fundus into the endometrial cavity. Three cannulas were evaluated: 1) the Cohen cannula with hold and no-hold techniques, 2) the BARD cervical cannula (dual intrauterine and intracervical balloons), and 3) the Harris-Kronner uterine manipulator-injector catheter with an intrauterine balloon. Intrauterine pressures were monitored while warm saline was infused. The studies were performed with the tubes obstructed, and measurements of peak attainable intrauterine pressures were recorded. Data were analyzed by t test, with significance set at P < .05. RESULTS: Peak intrauterine pressures for the four groups were as follows: 1) Cohen cannula, not holding, 40.7 +/- 5.1 mmHg; 2) Cohen cannula, holding in place, 63.6 +/- 5.3 mmHg; 3) BARD cannula, 112.4 +/- 3.5 mmHg; and 4) Harris-Kronner cannula, 106.3 +/- 4.3 mmHg. The BARD and Harris-Kronner cannulas achieved significantly higher intrauterine pressures than either method of using the Cohen cannula (P < .001). There was no statistically significant difference between the BARD and Harris-Kronner cannulas. CONCLUSION: Significant differences in achievable intrauterine pressures were demonstrated among catheters in our in vitro model. Based on these findings, we believe that the BARD, Harris-Kronner, or other intrauterine balloon-type cannula should be used before diagnosing proximal tubal obstruction.

Ovarian surgery on the rabbit. Effect of cortex closure on adhesion formation and ovarian function.

Surgical reapproximation of serosal surfaces in an attempt to reduce adhesiogenesis remains a controversial issue. For the reproductive gynecologist, this tenet is especially appropriate to the ovarian cortical surface. Using a rabbit model (n = 22), an ovarian unipolar cautery incision was created, and surgical closure versus nonclosure was evaluated. Closure with continuous 6-0 polyglactin resulted in a significant increase in the degree of ovarian adhesion envelopment versus nonclosure (1.8 +/- 0.2 vs. 0.9 +/- 0.2, P less than .01). Surgical closure also resulted in a significant increase in the vascularity of the adhesions (P less than .05). Despite the increase in adhesion formation, ovarian function, as determined by the mean number of corpora lutea, pregnancies and the nidation index, was not different in sutured ovaries, unsutured ovaries or nonsurgically treated controls.

Laparoscopic clips. Evaluation of absorbable and titanium with regard to hemostasis and tissue reactivity.

Advanced laparoscopic techniques require laparoscopic means of providing hemostasis. We tested the hemostatic ability of laparoscopic surgical clips and their tissue reactivity as assessed by adhesion formation in an animal model. Twenty-six New Zealand white rabbits were randomized at laparotomy to one of three treatment groups: titanium surgical clips, absorbable surgical clips (both applied with a laparoscopic clip applicator) and chromic sutures of equal mass. Either the right fallopian tube was transected, with clips or sutures applied proximally and distally to control bleeding, or the clips or sutures were applied 5 mm apart and the tube transected. A clip or suture of the same material was placed on the midportion of the left fallopian tube. Necropsy was performed at 42 days, and each clip/suture site was scored for adhesions. All the materials were easily applied and effective in achieving hemostasis. The adhesion scores tended to be lower with the absorbable clips; however, there were no statistically significant differences between the groups. Laparoscopic clips are effective in providing hemostasis, are easily applied and cause no more adhesion formation than do conventional suture materials.

Effect of acute physiological elevations of insulin on circulating androgen levels in nonobese women.

Extreme pharmacological elevation of the circulating insulin level acutely lowers dehydroepiandrosterone sulfate (DHEAS) levels. To assess whether more physiological elevations in plasma insulin (due to exogenous infusion or endogenous secretion) would have similar effects, we examined the levels of DHEAS, androstenedione, testosterone, and free testosterone before and after euglycemic hyperinsulinemic and hyperglycemic hyperinsulinemic clamp studies. Studies were performed in women within 20% of ideal body weight after an overnight fast. Androgen levels were measured before and at the conclusion of studies in which either insulin was infused exogenously at 1 mU/kg.min or endogenous insulin secretion was stimulated for 2 h by elevation of the plasma glucose concentration by 125 mg/dL above basal levels by an exogenous glucose infusion. Basal plasma DHEAS (6.2 +/- 0.5 mumol/L) declined to 5.2 +/- 0.4 mumol/L (P less than 0.001) during the euglycemic insulin clamp, without any significant change in testosterone, free testosterone, or androstenedione. During the hyperglycemic clamp, DHEAS fell from 6.7 +/- 0.5 to 5.1 +/- 0.4 mumol/L (P less than 0.001) in response to endogenous hyperinsulinemia; plasma testosterone, free testosterone, and androstenedione did not change significantly. There was no correlation between the elevation in plasma insulin concentration and the fall in DHEAS during either the euglycemic or hyperglycemic clamps. However, the magnitude of fall of DHEAS was directly correlated with the initial DHEAS level in both the euglycemic (r = 0.51; P less than 0.05) and hyperglycemic (r = 0.75; P less than 0.01) studies. This association of hyperinsulinemia with a reduction of circulating levels of DHEAS, but not other C-19 steroids (e.g. testosterone and androstenedione) may reflect differential mechanisms by which DHEAS levels are regulated and suggests that insulin either inhibits its biosynthesis and/or secretion, or enhances its MCR.

Ureteral injuries at laparoscopy: insights into diagnosis, management, and prevention.

The increasing use of laparoscopy as a therapeutic method mandates a reappraisal of the risks involved. Complications frequently described include injuries to the large and small bowels, bladder, and blood vessels. The world literature reports only eight cases of ureteral injury at laparoscopy. In this report, we present five additional cases of ureteral injury occurring at laparoscopy, in addition to a summary of those previously reported. Patients tend to present in the early postoperative period (48-72 hours) with low back pain, abdominal pain, leukocytosis, and peritonitis. The diagnosis should be made by intravenous pyelography; if possible, the injury should be stented by either the retrograde or percutaneous route. The injuries, except for one apparent trocar injury, involved the use of electrocoagulation, both unipolar and bipolar. The injuries occurred most commonly near the uterosacral ligaments. In 38% (five of 13) of the cases, the laparoscopy was performed for treatment of endometriosis. Three of the 13 patients eventually lost renal function of the affected side; two of these underwent a nephrectomy. Because visualization of the ureter near the cervix at the time of laparoscopy is difficult, especially in the presence of disease, laparoscopic procedures in this area must be carried out with caution.

Pelvic trophoblastic implants after laparoscopic removal of a tubal pregnancy.

Laparoscopic removal of ectopic gestations is becoming increasingly popular. We present a case in which an early, unruptured ampullary ectopic pregnancy was identified clinically, removed during laparoscopy, and subsequently confirmed by pathology. The patient later presented with pain and with rising titers of beta-hCG. Laparotomy demonstrated multiple pelvic implants of trophoblastic tissue.

Hysteroscopic management of uterine bleeding.

Hysteroscopy provides a means of accurately diagnosing and treating most forms of abnormal uterine bleeding. Submucous myomas and endometrial polyps may be easily removed with the resectoscope. If the myomas are large, pre-treatment with GnRH agonists will shrink the tumours, and facilitate hysteroscopic removal. One third of patients undergoing hysteroscopic myomectomy will have recurrent symptoms that require intervention. In the absence of malignancy, and in patients not desiring fertility, persistent dysfunctional uterine bleeding may be treated by endometrial ablation. These patients should be pre-treated with either danazol or GnRH agonists. Success with these techniques approaches 85%, but information about the long-term outcome for the majority of the reported cases is not available. Complications include uterine perforation and damage of intra-abdominal structures, fluid and electrolyte imbalance including pulmonary oedema, and anaphylactic reactions to certain distention media (32% dextran 70). These procedures provide the gynaecologist with an effective means of treating abnormal uterine bleeding without the attendant morbidity of a hysterectomy.

Endometriosis-associated infertility. Treatment options.

Formulating a treatment plan for infertility associated with endometriosis is difficult due to the lack of a cause-and-effect relationship between the disease and infertility. Several molecular and cellular mechanisms have been postulated as playing roles in endometriosis-associated infertility; they are reviewed here. Several medical and surgical treatment options are discussed, including danocrine, medroxyprogesterone acetate and gonadotropin releasing hormone agonists. A combined medical and surgical approach and occasional expectant management remain the treatments of choice.

The value of endocervical curettage in the management of the patient with abnormal cervical cytologic findings.

Patients with adequate colposcopic examinations and dysplasia on the endocervical curettage specimen usually undergo further diagnostic evaluation. This study evaluated 712 patients and found the frequency of positive endocervical curettage specimens to be 17.6%. Cervical conization or hysterectomy specimens were examined in 66 cases with a positive endocervical curettage. Of these, 69.7% had histologic evidence of discontinuous dysplasia in the endocervical canal. The endocervical curettage specimens were grouped by the percentage of endocervical epithelium that was dysplastic: group 1, less than 10%; group 2, 10% to 50%; group 3, greater than 50%. Confirmed histologic endocervical involvement was 80%, 56%, and 60%, respectively. The involvement of the endocervical canal also increased with increasing grade of cervical intraepithelial neoplasia. Of the 66 cases examined with positive endocervical curettage specimens, 62.1% had grade 3 cervical intraepithelial neoplasia on the ectocervix. Seven patients had positive endocervical margins, with six of these occurring in grade 3 cervical intraepithelial neoplasia lesions. Two unsuspected cases of cervical malignancy were identified by endocervical curettage.