Ana A. Murphy

Treatment of endometriosis with the antiprogesterone mifepristone (RU486)

OBJECTIVEnTo evaluate the safety and efficacy of an antiprogesterone (mifepristone, RU486; Roussel-Uclaf, Romaineville, France) on endometriosis.nnnDESIGNnAn open, prospective clinical trial.nnnSETTINGnThe clinical practice of an academic faculty.nnnPATIENTSnNine women with endometriosis were studied.nnnINTERVENTIONSnRU486 (50 mg/d) was administered for 6 months.nnnMAIN OUTCOME MEASURESnDaily symptom inventories and urinary steroid metabolites were assessed before, during, and after treatment. Blood for hormone analysis was obtained weekly for 4 weeks and monthly thereafter. The extent of endometriosis, bone mineral density, circadian rhythm of cortisol, and LH pulsatility were determined before and after treatment. Safety laboratory measurements were made before and at 1, 2, and 6 months of treatment.nnnRESULTSnPelvic pain and uterine cramping improved in all patients. Endometriosis regressed by 55%. All patients exhibited endocrine features of anovulatory amenorrhea without hypoestrogenism. A rise in serum LH and T levels was observed during the first month of treatment and one patient developed an elevation of liver transaminases during the last month of treatment. All other measurements were unchanged.nnnCONCLUSIONnRU486 appears to be effective in improving the symptoms and causing regression of endometriosis in the absence of significant side effects.

Regression of uterine leiomyomata to the antiprogesterone RU486: dose-response effect.

OBJECTIVEnTo study the response of uterine leiomyomata to three daily doses of RU486 (5, 25, and 50 mg).nnnDESIGNnProspective nonrandomized trial of women with symptomatic leiomyomata.nnnSETTINGnPatients from the clinical practice of the authors at the University of California, San Diego Medical Center.nnnPATIENTSnTen patients with symptomatic leiomyomata previously reported after treatment with 50 mg of RU486 daily for 3 months. Eleven patients treated with 25 mg of RU486 daily and nine patients placed on 5 mg of RU486 daily for 12 weeks.nnnMAIN OUTCOME MEASURESnChanges in leiomyomata volume as measured with vaginal ultrasounds at baseline and monthly thereafter. Frequent blood samples for hematology, chemistry, and hormone levels were obtained. Twenty-four-hour urine collections for free cortisol and creatinine were obtained at baseline and at 12 weeks.nnnRESULTSnAll three doses induce ovarian acyclicity. Administration of 50 mg of RU486 decreases leiomyomata volume to 78.1% +/- 4.8% of baseline at 4 weeks, 60.5% +/- 6.6% at 8 weeks, and 51.0% +/- 9.2% after 12 weeks of treatment. Regressive response in patients treated with 25 mg of RU486 daily was 76.3% +/- 5.0% of baseline at 4 weeks, 54.0% +/- 5.1% at 8 weeks, and 44.0% +/- 5.0% after 12 weeks. At 5 mg of RU486 leiomyomata volume was 80.6% +/- 8.3% of baseline after 4 weeks, 63.7% +/- 14.6% after 8 weeks, and 74.4% +/- 19.8% after 12 weeks of therapy.nnnCONCLUSIONSnAlthough acyclicity is seen at all three doses, an effective dose to cause a clinically significant (50%) decrease in leiomyomata volume appears to be 25 mg daily.

Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis

OBJECTIVEnTo examine endocrine and clinical responses to long-term administration of RU486 in patients with endometriosis.nnnDESIGNnProspective open trial.nnnSETTINGnFaculty practice of the authors.nnnPATIENTS, PARTICIPANTSnSix normally cycling women with endometriosis were recruited.nnnINTERVENTIONSnSubjects received RU486 100 mg/d for 3 months.nnnMAIN OUTCOME MEASURE(S)nHormonal changes during RU486 were compared with control data obtained in the preceding cycle during the early follicular phase. Clinical responses were determined by patient assessment and second-look laparoscopy.nnnRESULTSnAll women became amenorrheic, and daily urinary levels of ovarian steroid metabolites remained acyclic. Mean luteinizing hormone (LH) (P less than 0.02) and LH pulse amplitude (P less than 0.05) were increased without changes in LH pulse frequency. An antiglucocorticoid effect was demonstrated by an increase in serum cortisol (P less than 0.01) and adrenocorticotropic hormone (P less than 0.05) levels. Treatment resulted in an improvement in pelvic pain in all subjects without significant change in the extent of disease as evaluated by follow-up laparoscopy.nnnCONCLUSIONSnDaily administration of RU486 results in acyclic ovarian function and improvement in the subjective painful symptoms of endometriosis.

The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: a prospective, randomized study.

OBJECTIVEnOur purpose was to examine the effects of RU 486 and leuprolide acetate on uterine artery blood flow and uterine volume.nnnSTUDY DESIGNnPatients were randomly assigned to group A (eight patients) receiving 25 mg of RU 486 daily for 3 months or group B (six patients) receiving 3.75 mg of leuprolide acetate monthly for 3 months. Uterine artery blood flow change was determined by resistive index by means of vaginal color Doppler ultrasonography. Uterine volume was measured before and during the study with abdominal ultrasonography.nnnRESULTSnBoth groups showed an increase in resistive index. Patients receiving RU 486 had uterine artery blood flow decreased by 40%, and those receiving leuprolide acetate had a 21% decrease. We noted a significant decrease in uterine volume compared with pretreatment in both groups at 3 months. There was no significant decrease between groups.nnnCONCLUSIONnBoth RU 486 (25 mg daily) and leuprolide acetate (3.75 mg monthly) are effective in decreasing blood flow to the uterus (increasing resistive index) and decreasing uterine volume at 3 months. A significant decrease in uterine artery blood flow may provide a mechanism for the decrease in uterine size and the decrease in uterine blood loss at the time of surgery.

Autoantibodies to markers of oxidative stress are elevated in women with endometriosis

OBJECTIVEnTo measure autoantibodies that recognize oxidatively modified proteins in the sera of women with surgically proven endometriosis.nnnDESIGNnProspective study.nnnSETTINGnTertiary care academic medical center.nnnPATIENT(S)nWomen undergoing surgery for endometriosis or tubal ligation.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nSerum and peritoneal fluid autoantibody titers to malondialdehyde-modified low-density lipoprotein, oxidized low-density lipoprotein, and lipid peroxide-modified rabbit serum albumin determined by ELISA. Correlation of autoantibody titers with revised American Fertility Society staging classification, symptoms, and morphologic type of endometriosis.nnnRESULT(S)nMean (+/-SEM) serum autoantibody titers (in optical density units) to the three antigens were as follows: [1] lipid peroxide-modified rabbit serum albumin, 0.49 +/- 0.12 units in the patients with endometriosis and 0.2 +/- 0.02 units in the controls; [2] oxidized low-density lipoprotein, 0.22 +/- 0.005 units in the patients with endometriosis and 0.18 +/- 0.006 units in the controls; and [3] malondialdehyde-modified low-density lipoprotein, 0.21 +/- 0.005 units in the patients with endometriosis and 0.16 +/- 0.003 units in the controls. There was no correlation between autoantibody titers and revised American Fertility Society stage, symptoms, or morphologic type of endometriosis. Peritoneal fluid did not contain autoantibodies to any of the three antigens.nnnCONCLUSION(S)nAutoantibodies to markers of oxidative stress were significantly increased in women with endometriosis. These findings strongly support our data demonstrating that women with endometriosis have enhanced oxidative stress.

Rapid regression of uterine leiomyomas in response to daily administration of gonadotropin-releasing hormone antagonist * †

Objective The efficacy of acute and sustained pituitary gonadotropin down-regulation by the Nal-Glu GnRH antagonist (Nal-Glu) was evaluated in the treatment of uterine leiomyomas. Design Prospective, open clinical trial. Patients Seven normally cycling women with symptomatic leiomyomas. Interventions Nal-Glu (50 μ g/kg per day) was administered subcutaneously for 3 months. Main Outcome Measures Baseline ultrasound examinations were obtained and repeated monthly throughout treatment. Each leiomyoma was mapped and measured in three dimensions. Blood samples were drawn daily for 7 days, weekly for 4 weeks, and monthly for the remaining 2 months. Results Mean leiomyoma size decreased 52.8 ± 7.3% (means ± SD) after 1 month of therapy and remained unchanged for the remainder of the study. Serum levels of E 2 (35.9 ± 11.8 to 9.3 ± 0.8 pg/mL, 131.7 ± 43.3 to 34.0 ± 1.4 pmol/L), estrone (37.3 ± 7.5 to 13.0 ± 2.5 pg/mL, 138.1 ± 27.7 to 48.1 ±9.1 pmol/L), and P (1.6 ± 1.1 to 0.3 ± 0.01 ng/mL, 5.0 ± 3.6 to 0.9 ± 0.04 nmol/L) declined rapidly (within 48 hours) and remained suppressed throughout treatment. Serum LH, FSH, andro-stenedione, T, and DHEA levels did not change significantly. In two subjects who did not have surgical removal, leiomyomas grew to original size within the 1st month off drug. Six patients remained amenorrheic and the other subject spotted during the last 2 months of therapy. Conclusions Continuous treatment with Nal-Glu induces immediate and sustained pituitary-gonadal down-regulation that results in regression in leiomyoma size. By circumventing GnRH agonist-induced pituitary-ovarian up-regulation, GnRH antagonists may prove to be superior tools in the medical management of leiomyomas.

Effect of low-dose oral contraceptive on gonadotropins, androgens, and sex hormone binding globulin in nonhirsute women*†

The effectiveness of a low-dose oral contraceptive (OC) in suppressing plasma levels of gonadotropins, ovarian, and adrenal androgens and stimulating sex hormone-binding globulin (SHBG) was evaluated prospectively in nonhirsute women. Thirty-three women ingested 35 micrograms of ethinyl estradiol and 1 mg of norethindrone beginning within day 1 to 5 of the menstrual cycle. Baseline levels of luteinizing hormone, follicle-stimulating hormone, total testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), and SHBG were obtained before ingestion of the OC and repeated after 3, 6 and, 9 months of OC use on day 1 to 5 of the OC cycle. A significant suppression of gonadotropin levels is seen in nonhirsute women. Sex hormone binding globulin is consistently stimulated by the low-dose OC. A significant suppression of T and DHEAS is observed. No change was seen in levels of A. The demonstrated effects become evident at 3 months and are maintained at 6 and 9 months.

Evidence for Oxidatively Modified Lipid-Protein Complexes in Endometrium and Endometriosis

OBJECTIVEnTo evaluate for the presence of oxidatively modified lipid-protein complexes in endometriosis and endometrium of women with endometriosis and controls.nnnDESIGNnControlled clinical study.nnnSETTINGnAcademic tertiary care center.nnnPATIENT(S)nWomen undergoing surgery for pelvic pain, infertility, endometriosis, or tubal ligation controls.nnnINTERVENTION(S)nBiopsy of endometrium and endometriosis.nnnMAIN OUTCOME MEASURE(S)nStaining with antibodies to oxidatively modified lipid proteins (HNE-7, MDA2), macrophages (HAM-56), and muscle cell actin (HHF-35).nnnRESULT(S)nBoth endometrium and endometriosis tissues contain stromal cells that immunostain with HAM-56 and show immunostaining (both intracellular and extracellular) with HNE-7 and MDA2. Some endometriotic implants show patchy staining with HHF-35. Endometrium was devoid of staining with HHF-35. Control staining with nonimmune sera in both tissues was also devoid of staining.nnnCONCLUSION(S)nThese data strongly implicate the occurrence of oxidative stress in endometriosis tissue. These data also suggest that oxidative modification is a normal physiological process in endometrium.

Macrophages, Oxidation, and Endometriosis

Abstract: Retrograde menstruation has been suggested to be the cause for the presence of endometrial cells in the peritoneal cavity. However, little is known about the events that lead to the adhesion and growth of these cells that ultimately result in endometriosis, considering the fact that the disease occurs only in certain women despite the common occurrence of retrograde menstruation in most women. We postulate that, in normal women, the endometrial cells and tissue that arrive in the peritoneal cavity during menstruation are effectively removed by macrophages that are chemoattracted and become resident tissue macrophages in the peritoneal cavity. In contrast, the peritoneal macrophages in women with endometriosis are nonadherent and ineffectively scavenged, resulting in the sustained presence and growth of the endometrial cells. We also postulate that the peritoneal fluid is not a passive reservoir of the factors secreted by cells of the peritoneum, but actively promotes endometriosis. The peritoneal fluid is rich in lipoproteins, particularly low‐density lipoprotein, which generates oxidized lipid components in a macrophage‐rich inflammatory milieu. The oxidants exacerbate the growth of endometriosis by inducing chemoattractants such as MCP‐1 and endometrial cell growth‐promoting activity. We provide evidence for the presence of oxidative milieu in the peritoneal cavity of women with endometriosis, the nonscavenging properties of macrophages that are nonadherent, and the synergistic interaction between macrophages, oxidative stress, and the endometrial cells. For example, the peritoneal fluid lipoproteins of subjects with endometriosis have increased the propensity to undergo oxidation as compared with plasma lipoproteins, and the subjects also have increased titer of autoantibodies to oxidatively modified proteins. If the oxidative proinflammatory nature of the peritoneal fluid is an important mediator of endometriosis growth, anti‐inflammatory agents and antioxidants might afford protection against endometriosis.

Clinical Aspects of Endometriosis

Abstract: Endometriosis is one of the most commonly encountered gynecologic diseases requiring medical and/or surgical therapy. It is a leading cause of hysterectomy in the United States and has significant associated morbidity. The most frequent symptoms of genital tract endometriosis are dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Endometriosis occurs in the pelvis, most commonly the ovaries and the dependent areas covered with peritoneum. Diagnosis requires surgical intervention and is usually made by laparoscopy. In women being evaluated for pelvic pain, the diagnosis of endometriosis is made frequently (40‐60%) and varies with the population being studied. Infertility and endometriosis have long been associated. Although women with infertility may have pelvic pain, subfertility (20‐30%) can be the only presenting symptom. In asymptomatic women, the diagnosis of endometriosis ranges from 2% to 22% of reproductive‐age women. Its true incidence and natural history remain to be clarified. Endometriosis is a significant public health issue because of the large number of women it affects and the significant morbidity associated with this disease.