Rodolphe Maheux

Laparoscopic Surgery in Infertile Women with Minimal or Mild Endometriosis

Background Minimal or mild endometriosis is frequently diagnosed in infertile women. It is often treated by resection or ablation of the lesions, but whether this improves fertility has not been established. We carried out a randomized, controlled trial to determine whether laparoscopic surgery enhanced fecundity in infertile women with minimal or mild endometriosis. Methods We studied 341 infertile women 20 to 39 years of age with minimal or mild endometriosis. During diagnostic laparoscopy the women were randomly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only. They were followed for 36 weeks after the laparoscopy or, for those who became pregnant during that interval, for up to 20 weeks of pregnancy. Results Among the 172 women who had resection or ablation of endometriosis, 50 became pregnant and had pregnancies that continued for 20 weeks or longer, as compared with 29 of the 169 women in the diagnostic-laparoscopy group (cumulative probabilities, 30....BACKGROUND: Minimal or mild endometriosis is frequently diagnosed in infertile women. It is often treated by resection or ablation of the lesions, but whether this improves fertility has not been established. We carried out a randomized, controlled trial to determine whether laparoscopic surgery enhanced fecundity in infertile women with minimal or mild endometriosis. METHODS: We studied 341 infertile women 20 to 39 years of age with minimal or mild endometriosis. During diagnostic laparoscopy the women were randomly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only. They were followed for 36 weeks after the laparoscopy or, for those who became pregnant during that interval, for up to 20 weeks of pregnancy. RESULTS: Among the 172 women who had resection or ablation of endometriosis, 50 became pregnant and had pregnancies that continued for 20 weeks or longer, as compared with 29 of the 169 women in the diagnostic-laparoscopy group (cumulative probabilities, 30.7 percent and 17.7 percent, respectively; P=0.006 by the log-rank test). The corresponding rates of fecundity were 4.7 and 2.4 per 100 person-months (rate ratio, 1.9; 95 percent confidence interval, 1.2 to 3.1). Fetal losses occurred in 20.6 percent of all the recognized pregnancies in the laparoscopic-surgery group and in 21.6 percent of all those in the diagnostic-laparoscopy group (P=0.91). Four minor operative complications (intestinal contusion, slight tear of the tubal serosa, difficult pneumoperitoneum, and vascular trauma) were reported (three in the surgery group and one in the control group). CONCLUSIONS: Laparoscopic resection or ablation of minimal and mild endometriosis enhances fecundity in infertile women.

Reversible hypogonadism induced by a luteinizing hormone-releasing hormone (LH-RH) agonist (Buserelin) as a new therapeutic approach for endometriosis

Ten women with endometriosis (stages I to IV) were treated with twice-daily subcutaneous injections of 200 micrograms of (D-Ser[TBU]6-des-Gly-NH2(10] luteinizing hormone-releasing hormone ethylamide (Buserelin) for 5 days followed by 400 micrograms intranasally three times daily for 25 to 31 weeks. Serum follicle-stimulating hormone levels returned to basal values on the second day of treatment, and serum luteinizing hormone levels progressively decreased to normal within 4 weeks. Serum estradiol decreased below early follicular phase levels within 7 to 30 days and continued to decrease to castrate levels. Light to moderate estrogen withdrawal bleeding was followed by amenorrhea with occasional bleeding or spotting in four women. Abdominal pain and dyspareunia disappeared or were ameliorated after 2 months of treatment. Resorption of endometrial implants was demonstrated by laparoscopy, and endometrial biopsy revealed atrophy or weak proliferation. Ovulation returned within 45 days, and two of four sexually active women became pregnant during cycles 3 and 5. The treatment was well accepted in spite of the expected hot flushes and vaginal dryness. Safety laboratory tests during and after treatment did not reveal any abnormalities. Reversible down-regulation of pituitary/ovarian function using repetitive luteinizing hormone-releasing hormone agonist administration can be a worthwhile approach to medical treatment of endometriosis.

Elevated concentration and biologic activity of monocyte chemotactic protein-1 in the peritoneal fluid of patients with endometriosis * † ‡

OBJECTIVE To estimate the concentration and the biologic activity of monocyte chemotactic protein-1 (MCP-1) in the peritoneal fluid (PF) of women with and without endometriosis. DESIGN A case control study was conducted. SETTING Gynecology clinic and Laboratories of endocrinology of reproduction and immunology. PATIENTS Women presenting for infertility, pelvic pain, or tubal ligation in which endometriosis was diagnosed at laparoscopy (n = 36) and normal fertile controls presenting for tubal ligation (n = 21). INTERVENTIONS Collection of PF via laparoscopy. MAIN OUTCOME MEASURES Determination of PF concentrations of MCP-1 by an ELISA and evaluation of its monocyte chemotactic activity using a human hystiocytic cell line (U937). RESULTS. The concentration of MCP-1 (median, range of values) was increased in the PF of endometriosis patients (283, 0 to 1,930 pg/mL; conversion factor to SI unit, 0.155) compared with the control group (140, 0 to 435 pg/mL). The most significant elevation of MCP-1 levels was found in the stage II of the disease (371, 200 to 1,930 pg/mL). An increased chemotactic activity for monocytes (mean number of migrating cells/mm2 +/- SD) also was found in stages I (1,460 +/- 312) and II (1,541 +/- 336) of the disease when compared with fertile controls (393 +/- 56). Forty percent to 53% of this activity was inhibited in the presence of an antibody specific to MCP-1. CONCLUSIONS These observations are consistent with previous data indicating increased leukocyte chemotaxis in the PF of patients with endometriosis and suggest that MCP-1 may play a relevant role in the peritoneal inflammatory reaction associated with the disease.

Luteinizing hormone-releasing hormone agonist and uterine leiomyoma: A pilot study☆

Ten women with 12 uterine leiomyomas ranging from 7.5 to 420 cc (mean, 112.6 +/- 39.4) were treated with subcutaneous injections of the luteinizing hormone-releasing hormone agonist buserelin, 200 micrograms three times daily for 1 week and then 500 micrograms daily for the rest of the 6-month treatment period. Following initial stimulation the pituitary ovarian axis was suppressed after 3 weeks of treatment with mean serum estradiol ranging between 17 and 36 pg/ml. Seven uterine leiomyomas had a marked regression in size following treatment with luteinizing hormone-releasing hormone agonist; two were undetectable and the volume of the other five diminished by an average of 80%. One tumor did not respond to treatment, two regressed by 25%, and two, following an initial reduction of 65% and 50%, reenlarged during the last 2 months of treatment to 75% and 100% respectively of their initial volume. Luteinizing hormone-releasing hormone agonist is the first medication demonstrated effective in reducing the size of uterine myomas.

Characteristics Related to the Prevalence of Minimal or Mild Endometriosis in Infertile Women

The objective of this case-control study is to identify factors associated with the prevalence of minimal or mild endometriosis among infertile women. Cases (N = 329) were women diagnosed by laparoscopy with minimal or mild endometriosis and without any other factors explaining their infertility. Controls (N = 262) were women in whom the infertility remained unexplained after a diagnostic laparoscopy. Selected characteristics were documented by means of a face-to-face interview before the laparoscopy. The prevalence of minimal or mild endometriosis was higher in women age 25 years or older, in those who reported menarche at the age of 13 years [prevalence odds ratio (POR) = 1.63; 95% confidence interval (CI) = 1.02–2.60] or older (POR = 1.73; 95% CI = 1.07–2.78), menstrual cycles of 27 days or less (POR = 1.63; 95% CI = 1.02–2.60), or caffeine intake of 300 mg per day or more (POR = 1.33; 95% CI = 0.91–1.94). The prevalence of minimal or mild endometriosis was inversely related to body mass index. Parous women were less likely to have endometriosis (POR = 0.61; 95% CI = 0.39–0.96) than were nulliparous women. Education, duration of infertility, and smoking status were not related to the presence of endometriosis. (Epidemiology 1998;9:504–510)

Fecundity of Infertile Women with Minimal or Mild Endometriosis And Women with Unexplained Infertility

OBJECTIVE To assess whether infertile women with minimal or mild endometriosis have lower fecundity than women with unexplained infertility. DESIGN Prospective cohort study. SETTING Twenty-three infertility clinics across Canada. PATIENT(S) Three hundred thirty-one infertile women aged 20-39 years. INTERVENTION(S) Diagnostic laparoscopy for infertility. Infertile women with minimal or mild endometriosis (n = 168) were compared with women with unexplained infertility (n = 263). Both groups were managed expectantly. The women were followed up for 36 weeks after the laparoscopy or, for those who became pregnant, for up to 20 weeks of the pregnancy. MAIN OUTCOME MEASURE(S) Fecundity refers to the probability of becoming pregnant in the first 36 weeks after laparoscopy and carrying the pregnancy for > or = 20 weeks. The fecundity rate is the number of pregnancies per 100 person-months. RESULT(S) Fecundity was 18.2% in infertile women with minimal or mild endometriosis and 23.7% in women without endometriosis (log-rank test). The fecundity rate was 2.52 per 100 person-months in women with endometriosis and 3.48 per 100 person-months in women with unexplained infertility. The crude and adjusted fecundity rate ratios were 0.72 and 0.83 (95% confidence interval = 0.53-1.32), respectively. CONCLUSION(S) The fecundity of infertile women with minimal or mild endometriosis is not significantly lower than that of women with unexplained infertility.

Stimulation of Macrophage Migration Inhibitory Factor Expression in Endometrial Stromal Cells by Interleukin 1, beta Involving the Nuclear Transcription Factor NFκB

Abstract Endometriosis, the ectopic development of endometrial tissue, is, particularly in peritoneal endometriosis, believed to result from tubal reflux of menstrual tissue. The release of cytokines and growth factors by refluxed endometrial cells in response to peritoneal inflammatory stimuli may enhance the capability of endometrial cells to implant and grow into the peritoneal host tissue. Herein we report that interleukin 1 (IL1), a major proinflammatory cytokine that is overproduced by endometriosis women-derived peritoneal macrophages and found in elevated concentrations in the peritoneal fluid of patients with endometriosis, stimulates the synthesis and the secretion of macrophage migration inhibitory factor (MIF) by human endometrial stromal cells. IL1B (0.1–100 ng/ml) exerted dose- and time-dependent effects of MIF protein secretion and mRNA synthesis, as shown by ELISA and reverse transcription-polymerase chain reaction, respectively. IL1B appeared to induce MIF gene transcription via the κB nuclear transcription factor (NFκB), as shown by electrophoretic mobility shift assay and Western blot analysis of IκB phosphorylation. Curcumin (10−8 M), which is known for inhibiting NFκB activation, inhibited IL1B-induced MIF secretion as well as NFκB nuclear translocation and DNA binding. Taken together, these findings clearly show that IL1B up-regulates the expression of MIF in endometrial stromal cells in vitro and acts via NFκB. This may play an important role in the physiology of the human endometrium and the pathophysiology of endometriosis considering the immunomodulatory properties of MIF as well as its role in cell growth, angiogenesis and tissue remodeling.

Use of intranasal luteinizing hormone-releasing hormone agonist in uterine leiomyomas

Nine women harboring uterine leiomyomas have been treated with subcutaneous injections and then with intranasal insufflation of luteinizing hormone-releasing hormone agonist for a total treatment period of 6 months. After initial stimulation, mean serum estradiol progressively decreased and stabilized at 36.8 +/- 4.9 pg/ml for the rest of the treatment period. The volume of uterine leiomyomas has been reduced by an average of 71%. Side effects and hot flushes were less severe and better tolerated than reported after sole subcutaneous administration.

Efficacy of intranasal or subcutaneous luteinizing hormone-releasing hormone agonist inhibition of ovarian function in the treatment of endometriosis☆

We have previously reported reversible hypogonadism induced by the intranasal administration of the luteinizing hormone-releasing hormone agonist buserelin as a new therapeutic approach for endometriosis. Thirteen patients were randomized to receive intranasal buserelin (400 micrograms 3 times a day) or subcutaneous buserelin injection (200 micrograms once daily) for a 6- to 9-month period. Both routes of administration were effective in inhibiting serum estradiol levels to near the menopausal range after 1 month of treatment. The two dosage regimens had also a comparable efficacy in alleviating endometriosis symptoms and in reducing the revised American Fertility Society scoring at laparoscopic examination. The implant score mainly decreased by more than 70%. The occurrence of side effects was similar in both groups, and side effects were mainly hot flushes, dyspareunia secondary to decreased vaginal secretion, and decreased libido. Results of hemogram, urinalysis, and serum biochemical and hormonal tests remained in the normal range. The ovulatory cycle rapidly returned after the cessation of treatment, and three pregnancies occurred in six previously infertile patients. Intranasal and subcutaneous buserelin were well accepted and equally effective in inhibiting the pituitary-ovarian function, which caused mild menopausal symptoms but an important regression of endometriosis.

Oral contraceptives and prolactinomas: A case-control study

The increase in the number of newly diagnosed cases of prolactinomas seems to coincide with the use of oral contraceptives during the past two decades. The following retrospective case-control study was undertaken in an attempt to disprove a null hypothesis of relationship between oral contraceptive use and prolactinomas. Each of 70 patients operated upon for removal of a prolactinoma was closely matched for age, gravidity, and year of final diagnosis with one patient in each of three control groups. The control groups selected were constituted, respectively, of patients with secondary amenorrhea and normal prolactin levels, patients with normal ovulatory cycles consulting for infertility, and subjects without medical or gynecologic problems. No statistically significative differences were found in the exposure rates to oral contraceptives among four groups. This study thus failed to reveal a significant association between prolactinomas and oral contraceptives but, given the sample size, a relative risk lower than 3.32 cannot be demonstrated or disproved.