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Objective: To investigate the expression of heparanase-1, an endoglycosidase that degrades heparan sulfate proteoglycans, in eutopic and ectopic endometrial tissues from women with endometriosis., Design: An immunohistochemical study., Setting: Academic research laboratory and a private infertility clinic affiliated with a university medical center., Patient(s): Premenopausal women undergoing laparoscopy for endometriosis., Intervention(s): None., Main Outcome Measure(s): Expression of heparanase-1 analyzed by immunohistochemical staining in 91 eutopic and 14 ectopic endometrial specimens., Result(s): We found that 17% (4/24) of the eutopic endometrial specimens in the early proliferative phase and 32% (9/28) of the samples in the midproliferative phase were heparanase-1 positive. However, >or=80% of eutopic endometrial specimens at late proliferate phase and at luteal phase were heparanase-1 positive. Twelve of 14 ectopic endometriotic specimens stained heparanase-1 positive. Comparison of heparanase-1 expression in paired eutopic and ectopic endometrial tissues revealed that 5 of 6 ectopic specimens in the early proliferative phase were heparanase-1 positive, whereas only 1 eutopic specimen was heparanase-1 positive. In comparison with our recent study of heparanase-1 expression in normal endometrium, we found that there was no significant difference in heparanase-1 expression in the eutopic endometrium from women with or without endometriosis., Conclusion(s): Heparanase-1 was differentially expressed in the eutopic endometrium in the different menstrual phases. Heparanase-1 was highly expressed in the ectopic endometriotic lesions regardless of their menstrual phases, suggesting that the local environment is responsible for increased heparanase-1 expression.

Objective: To quantitate antiapoptotic and proapoptotic gene expression in endometrial cells (ECs) of women with and without endometriosis., Design: Determination of transcript abundance (TA) of apoptosis-regulating genes in eutopic and ectopic endometrial cells., Setting: Institute for the Study and Treatment of Endometriosis, Chicago, Illinois, and university-based research laboratories., Patient(s): Women with (n = 10) and without (n = 6) endometriosis., Intervention(s): None., Main Outcome Measure(s): Quantitative virtually multiplexed transcript abundance measurement (VMTA) of the BCL2, BCLxL, defender against cell death-1 (DAD-1), BCLxS, P53, Caspase-1, and proliferating cell nuclear antigen (PCNA) genes., Result(s): The TA ratio of antiapoptotic to proapoptotic isoforms of the BCL-X gene favors survival in eutopic and ectopic ECs from women with endometriosis, but not control ECs. This was found throughout the menstrual cycle for ectopic ECs. Eutopic but not ectopic ECs also expressed increased TA of the antiapoptotic DAD-1 gene in endometriosis. Eutopic and ectopic ECs from women with endometriosis expressed decreased TA of p53 and Caspase-1 compared to ECs from women without endometriosis. Expression of these genes was not correlated with the proliferative state of ECs based on TA of the PCNA gene., Conclusion(s): Dysregulation in expression of pro- and antiapoptotic regulatory genes characterizes eutopic and ectopic ECs from women with endometriosis. These results are consistent with apoptotic resistance and enhanced survival of ECs in endometriosis.

Objective: To compare controlled ovarian hyperstimulation-intrauterine insemination (COH-IUI) or IVF-ET pregnancy rates per cycle (PR) and cycle and cumulative fecundity (f and cf) with COH-IUI or IVF-ET in endometriosis., Design: Retrospective analysis., Setting: Endometriosis research institute., Patient(s): Women with endometriosis and infertility (n = 313) who underwent consecutive COH-IUI (202 patients, 648 cycles), IVF-ET (111 patients, 139 cycles), or IVF-ET after failed COH-IUI (56 patients, 68 cycles)., Intervention(s): None., Main Outcome Measure(s): Crude PR and life table-estimated f and cf., Result(s): With COH-IUI, 69 patients conceived; 65 conceived with IVF-ET; and 30 conceived with IVF-ET after COH-IUI (PR 11%, 47%, and 44%). With COH-IUI, six-cycle cf was 41%, and f for cycles 1-6 was 15%, 12%, 8%, 7%, 7%, and 0. With IVF-ET, three-cycle cf was 73%, whereas f for cycles 1-3 was 47%, 27%, and 33%. First-cycle f with IVF-ET was significantly higher than cf of six COH-IUI cycles. When the data were stratified according to the stage of endometriosis and women's age, the benefit of IVF over COH was even more pronounced. Prior COH-IUI failure did not adversely affect IVF-ET outcome., Conclusion(s): In endometriosis, PR, f, and cf are significantly higher with IVF-ET than COH-IUI, especially in stage IV and in women >38 years of age. Considering adverse effects of prolonged ovarian stimulation on endometriosis, IVF-ET should be the first-line approach in the management of infertility in this disease. If COH-IUI is attempted, it should not exceed three to four cycles.

Objective: To evaluate spontaneous apoptosis in single-cell suspensions of eutopic and ectopic endometrium from women with endometriosis and in eutopic endometrium from fertile controls without endometriosis., Design: Paired specimens of eutopic and ectopic endometrial tissue from patients with endometriosis and eutopic endometrium from controls were assessed for spontaneous apoptosis., Setting: Institute for the Study and Treatment of Endometriosis and university-based research laboratories., Patient(s): Fertile controls (n = 10) and women with untreated endometriosis (n = 16)., Intervention(s): None., Main Outcome Measure(s): Spontaneous apoptosis assessed with an ELISA-based cell death detection kit., Result(s): Spontaneous apoptosis (monitored by absorbance) of eutopic endometrium from patients with endometriosis and fertile controls was 0.63 +/- 0.1 and 1.43 +/- 0.11, respectively. Among patients with endometriosis, spontaneous apoptosis of ectopic endometrium was 0.26 +/- 0.06. Decreased apoptosis of ectopic versus eutopic endometrium was observed independent of cycle phase., Conclusion(s): The susceptibility of endometrial tissue to spontaneous apoptosis is significantly lower in women with endometriosis than in fertile controls. We suggest that decreased susceptibility of endometrial tissue to apoptosis contributes to the etiology or pathogenesis of endometriosis.

Objective: To compare the ability of peripheral blood monocytes (PBM) and peritoneal macrophages (PM) to mediate the in vitro cytolysis of endometrial cells from eutopic and ectopic endometrium in women with endometriosis., Design: Prospective study of immune function., Setting: Institute for the Study and Treatment of Endometriosis and university-based research laboratories., Patient(s): Twenty-four women with endometriosis (15 in stage I/II, 9 in stage III/IV) and 4 patients treated with GnRH agonists., Intervention(s): Peritoneal fluid and peripheral blood were sampled and eutopic and ectopic endometrium were biopsied during diagnostic laparoscopy., Main Outcome Measure(s): Lysis of autologous endometrial cells., Result(s): Peripheral blood monocytes were significantly more cytolytic than peritoneal macrophages against autologous uterine endometrial cells. However, PBM and PM displayed a similar degree of cytolysis against a hepatoma cell line. Ectopic endometrial cells were significantly more resistant to cytolysis by autologous PBMC than were matched eutopic endometrial cells, and were completely resistant to cytolysis by autologous PM., Conclusion(s): The reduced capacity of PM from women with endometriosis to mediate the destruction of endometrial cells coupled with the increased resistance of ectopic endometrial cells to macrophage-mediated cytolysis may facilitate the survival of these cells within the peritoneal cavity of women with endometriosis.

Objective: To evaluate the effectiveness of N-telopeptides and E2 in monitoring bone turnover during GnRH agonist- (GnRH-a) or danazol-induced hypoestrogenism., Design: Comparative, nonrandomized prospective study., Setting: Institute for the Study and Treatment of Endometriosis., Patient(s): Premenopausal women undergoing ovarian suppression with GnRH-a (n = 16) or danazol (n = 9)., Intervention(s): Serum and urine samples were collected and bone mineral density was measured before, during, and after treatment., Main Outcome Measure(s): N-telopeptide excretion, serum E2, and bone mineral density at L1 to L4 and femoral neck., Result(s): During treatment in the GnRH-a group, mean E2 levels were 53% below and N-telopeptides were 38% above the mean baseline. At 1 month post-treatment, L1 to L4 bone mineral density decreased by 3.85%. In the danazol group, E2, N-telopeptides and L1 to L4 bone mineral density changed nonsignificantly in the opposite direction with the mean 1.25% increase in L1 to L4 at 1 month post-treatment. In combined groups, L1 to L4 bone mineral density better correlated with other measures than femoral neck bone mineral density. N-telopeptide excretion was more predictive of L1 to L4 change, with correlation the highest between N-telopeptides at month 4 and bone mineral density at month 1 afterward, while E2 appeared more predictive of the less reliable femoral neck bone mineral density. Individual exceptions to the model of an E2 threshold for bone loss were observed. Also noted were high correlation between on-therapy levels of E2 and N-telopeptides, as well as the presence of a 1-month time lag between E2 and N-telopeptide changes., Conclusion(s): Bone density decreases during GnRH-a and may slightly increase during danazol treatment. However, E2 threshold for bone loss varies individually. N-telopeptides predict changes in bone mineral density at L1 to L4 better than E2.

Objective: To investigate the capacity of peripheral blood monocytes (PBM) from women with endometriosis to secrete tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) IL-6, IL-8, and IL-10., Design: Peripheral blood monocytes were cultured in the presence and absence of lipopolysaccharide for 24 hours before assessment of cytokines in supernatants by enzyme immunoassay., Setting: Institute for the Study and Treatment of Endometriosis and university-based research laboratories., Patients and Participants: Fertile controls, n - 10; women with endometriosis, n = 20., Interventions: None., Results: Basal synthesis of TNF-alpha, IL-6, and IL-8 and the lipopolysaccharide-stimulated synthesis of TNF-alpha by PBM from women with endometriosis was significantly greater in comparison to that of fertile controls. Endometriosis had no effect on the basal or stimulated synthesis of IL-10., Conclusions: These data show that endometriosis is associated with increased basal and stimulated synthesis and secretion of several different cytokines by PBM. Each of the cytokines found to be affected has the capacity to play a role in the symptomatology or pathogenesis of the disease.

Objective: To evaluate basal (constitutive) and stimulated synthesis of tumor necrosis factor alpha (TNF alpha), interleukin (IL)-8, IL-10 by peritoneal macrophages (PM) in women with endometriosis., Design: Peritoneal macrophages were cultured in the presence or absence of lipopolysaccharide (LPS) for 24 hours. Peritoneal fluids (PF) and PM supernatants were assayed for cytokines using ELISA., Setting: Institute for the Study and Treatment of Endometriosis and university-based research laboratories., Subjects: Fertile controls undergoing tubal ligation (n = 8) and women with endometriosis (n = 17)., Intervention: Peritoneal fluid samples were obtained at the time of diagnostic laparoscopy (endometriosis group) or laparoscopy for tubal ligation; both were performed in the midluteal phase of the cycle., Results: Both basal and LPS stimulated production of TNF alpha, IL-8, and IL-10 by the PM were elevated significantly in women with endometriosis as compared with the fertile controls., Conclusions: This study demonstrated that cytokines TNF alpha, IL-8, and IL-10 are synthesized at greater than normal levels by basal and stimulated PM from women with endometriosis. The levels of TNF alpha and IL-8 correlated with the levels in the PF, suggesting that PM are the principal source of these cytokines in the PF.

Objectives: To analyze IVF cycle parameters, including pregnancy rates (PR), in women with and without endometriosis and to evaluate the effect of the stage and activity of endometriosis and of autoantibodies., Design: A retrospective analysis of 237 consecutive IVF cycles (193 patients), 119 in women with and 118 without endometriosis. The endometriosis group was further subdivided according to the stage and activity of the disease and autoantibody positivity., Setting: Hospital-based and freestanding IVF programs with the same IVF team., Patients: One hundred ninety-three women of reproductive age undergoing IVF; 84 had prior diagnosis of endometriosis, and 109 had other indications for IVF. Within the endometriosis group, 40 did and 44 did not have evidence of active disease. Autoantibodies were measured in 50 patients., Interventions: The IVF protocol was standard with GnRH agonist administered from the midluteal phase of the preceding cycle. Variables included the method of ET and the use of corticosteroids., Main Outcome Measures: Number of follicles produced, number of eggs retrieved, fertilization rates, number of embryos transferred, and PR per transfer., Results: There was no difference between groups in the response to stimulation, number of oocytes retrieved, number fertilized, and number cleaved. The overall PR was 27% per transfer; it was similar in women with and without endometriosis (29% and 25%, respectively). There was also no difference in PR according to the stage or activity of the disease. However, PR in autoantibody-positive and -negative patients were significantly different (22.9% and 45.7%, respectively). Among autoantibody-positive patients treated with corticosteroids, 8 of 10 conceived., Conclusions: This study confirms previous reports that IVF success rates are comparable in women with and without endometriosis regardless of the activity and stage of the disease. However, our study also indicates that autoantibodies may affect adversely implantation of embryos and that this effect can be overcome by administration of corticosteroids.

Objective: To investigate the capacity of monocytes from women with endometriosis to influence endometrial cell proliferation., Design: Uterine endometrial cells were cultured in the presence and absence of autologous blood monocytes for 72 hours before assessment of endometrial cell proliferation by thymidine incorporation., Setting: Patients were tested at initial presentation for evaluation of infertility and/or endometriosis., Patients, Participants: Fertile controls, n = 17; infertile controls, n = 9; untreated endometriosis, n = 29., Interventions: None., Results: Endometrial cell proliferation was enhanced significantly by blood monocytes in patients with endometriosis but was suppressed significantly by blood monocytes in fertile controls. Endometrial cell proliferation was not affected significantly by blood monocytes in infertile controls analyzed as a group, but a subset of infertile patients also showed enhancement of endometrial cell proliferation by blood monocytes., Conclusions: Blood monocytes from patients with endometriosis and a subset of patients with unexplained infertility enhance autologous endometrial cell proliferation, whereas blood monocytes from fertile patients suppress endometrial cell proliferation. The capacity of monocytes to enhance endometrial cell proliferation appears to require both monocyte-derived factors that stimulate endometrial cell proliferation and endometrial cells capable of responding to those stimulatory factors. If either of these factors is absent, monocytes either suppress or have no effect on endometrial cell proliferation.

Objectives: To evaluate sequential changes in fetal heart rate (FHR) during the first trimester of well-timed pregnancies resulting from infertility treatment and to correlate the data with fetal growth curve and beta-hCG levels., Design: Serial measurements of FHR, crown-rump length (CRL) and beta-hCG at weekly intervals throughout the first trimester in 67 consecutive conceptions, resulting from infertility treatment. The day of preovulatory LH surge or of exogenous hCG administration was known in each case., Setting: Hospital based and private assisted reproductive technology centers., Results: Mean FHR was 108 +/- 12, 26 to 30 days after LH/hCG (5 weeks, 4 days from last menstrual period [LMP]) in embryos 3 +/- 0.3 mm in size; the FHR gradually increased, reaching a peak of 177 +/- 10 on days 51 to 55 (9 weeks from LMP) in embryos of 23 +/- 5.5 mm; it decreased to 156 +/- 5 on days 76 to 80 (12 weeks, 5 days from LMP) in embryos of 62 +/- 5.7 mm. There was, previously not reported, high level correlation between beta-hCG and FHR during the entire first trimester and positive correlation between FHR and CRL during the first 55 days from conception., Conclusions: During the first trimester of pregnancy, FHR closely follows beta-hCG pattern. Correlation between beta-hCG and FHR is an interesting phenomenon that needs further investigation.

Objective: To assess the activation status of peritoneal macrophages from women with endometriosis., Design: Peritoneal macrophages from patients undergoing laparoscopy were tested for cytotoxic activity against a cultured hepatoma cell line., Setting: Patients were tested at initial laparoscopy or at the completion of therapy., Patients and Participants: Fertile controls (n = 27), infertile controls (n = 20), untreated endometriosis (n = 43), danazol-treated endometriosis (n = 22), and gonadotropin-releasing hormone agonist (GnRH-a)-treated endometriosis (n = 13) were tested., Interventions: Danazol (800 mg/d) or GnRH-a therapy for 6 months., Results: Cytotoxicity was elevated in stage I and II endometriosis (P less than 0.02) and in infertile controls (P less than 0.05) compared with fertile controls. Cytotoxicity in stage III and IV endometriosis was lower (P less than 0.02) than in stage I and II endometriosis. Indomethacin in vitro increased cytotoxicity (P less than 0.05) in stage III and IV endometriosis but not in the other groups tested. Cytotoxicity in danazol or GnRH-a-treated patients was increased (P less than 0.05 or greater) compared with untreated patients with comparable stage of disease., Conclusions: Peritoneal macrophage cytotoxicity in women with endometriosis is affected by (1) the extent of endometriosis, (2) prostaglandin metabolism, and (3) treatment with danazol or GnRH-a.

The effectiveness of ovulation induction with clomiphene citrate or human menopausal gonadotropins was evaluated in 52 infertile women with stage I or stage II endometriosis and ovulatory dysfunction: anovulation or luteinized unruptured follicle (LUF) syndrome before (group I) and after (group II) danazol treatment. The incidence of anovulation and LUF in the endometriosis population was 9% and 34%, respectively. In group I, 10 of 36 patients (27.8%) conceived, with an average of 17.6 induction cycles per pregnancy. In group II, 21 of 30 patients (70%) conceived, with an average of 4.5 cycles per pregnancy (difference significant at P less than 0.001). There was no difference in the average number of ovulation induction cycles per patient between groups I and II (4.9 and 3.1, respectively). Of 14 patients who did not conceive in group I and crossed over to group II, 9 (64.3%) conceived (not different from group II). Spontaneous abortion rates were 20% in group I and 14% in group II. These results indicate that mild endometriosis may interfere with conception through mechanisms other than ovulatory dysfunction and that treatment with danazol appears to more than double the fertility rate.