Ming-Yih Wu

The role of cytokines in endometriosis.

PROBLEM:  To review the literature on the role of peritoneal cytokines in the pathogenesis and endometriosis‐related infertility.

Peritoneal Cellular Immunity and Endometriosis

PROBLEM: An immunologic basis has long been considered to be very important in the pathogenesis of endometriosis. Interactions of the peritoneal cells, which comprise macrophages, B cells, T cells, natural killer (NK) cells, and retrograde endometrial cells, are critical, but remain controversial, for exploring the pathogenesis of endometriosis. METHOD OF STUDY: Accumulated data from the literature were reviewed, and our data were analyzed.

The relationship between anti-Müllerian hormone, androgen and insulin resistance on the number of antral follicles in women with polycystic ovary syndrome

BACKGROUND Anti-Müllerian hormone (AMH) is a biomarker that predicts the number of antral follicles and is involved in follicle arrest for women with polycystic ovary syndrome (PCOS). We investigated the association between the characteristic hyperandrogenemia, insulin resistance (IR), AMH, and the morphology and size of ovaries for women with PCOS. METHODS A total of 99 Taiwanese women with PCOS who were willing to undergo vaginal ultrasonography were enrolled in this cross-sectional study. RESULTS The number of antral follicles and the ovarian volume showed a significant correlation with AMH, total testosterone and the free androgen index, but not with age, body mass index (BMI) or the homeostasis model assessment of insulin resistance (HOMA-IR). AMH had a significant negative association with both BMI and HOMA-IR. Multiple stepwise regression analysis demonstrated that AMH, BMI and total testosterone were independently related to the number of antral follicles. AMH and total testosterone were the main determinants for ovarian volume in a stepwise regression model. CONCLUSIONS Our results suggest that not only the AMH level, but also obesity, IR and elevated androgen levels may relate to the development of the large size of antral follicle pool and ovarian volume in women with PCOS. Obesity and IR may enhance the follicular excess through the dysregulation of AMH or through the pathway of hyperandrogenemia. These findings might partly explain why adequate body weight management and improvement in IR can improve the ovulatory function for women with PCOS.

Decrease in interferon gamma production and impairment of T-lymphocyte proliferation in peritoneal fluid of women with endometriosis.

OBJECTIVE Our purpose was to verify regional immune modulations and to test the effect of gonadotropin-releasing hormone agonist in women with endometriosis. STUDY DESIGN Concentrations of peritoneal cytokines, including interleukin-1 beta, interleukin-2, soluble interleukin-2 receptor, interleukin-6, granulocyte-monocyte colony-stimulating factor, interferon gamma, and tumor necrosis factor-alpha were compared in women with and without endometriosis. Peritoneal cytokine and interleukin-2 production were examined by adding various mitogens to peritoneal fluid mononuclear cells of women with advanced endometriosis before and after gonadotropin-releasing hormone agonist treatment. RESULTS A significant increase in peritoneal interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha and a decrease in interferon gamma were noted in women with endometriosis. After gonadotropin-releasing hormone agonist treatment interleukin-6 decreased and interferon gamma increased. A significant impairment of interleukin-2 production of peritoneal fluid mononuclear cells by phytohemagglutinin and pokeweed mitogen stimulation was demonstrated in endometriosis, and production could be restored after gonadotropin-releasing hormone agonist treatment. CONCLUSION These results indicate that regional immunologic dysfunction might be invoked in the disease process of endometriosis.

Assisted hatching increases the implantation and pregnancy rate of in vitro fertilization (IVF)-embryo transfer (ET), but not that of IVF-tubal ET in patients with repeated IVF failures

OBJECTIVE To assess the effect of augmenting IVF with assisted hatching in the treatment of patients with repeated IVF failures. DESIGN Prospective randomized study. SETTING Division of Reproductive Endocrinology and Infertility of National Taiwan University Hospital. PATIENT(S) From July 1993 to February 1996, 49 patients with repeatedly failed IVF were treated with assisted hatching and were compared with 51 control subjects without assisted hatching. INTERVENTION(S) Assisted hatching. MAIN OUTCOME MEASURE(S) Pregnancy rate and implantation rate per embryo after IVF-ET or IVF-tubal ET (TET) were measured. RESULT(S) The pregnancy rate (PR) in the assisted hatching group was found to be 36.7% compared with 19.6% in the control group, but the difference was not significant. When only patients receiving IVF-ET were considered, it was observed that the PR was significantly higher in the assisted hatching group than the control group (42.4% versus 16.1%). With IVF-TET however, the PR was found to be similar in both assisted hatching and control groups (25.0% and 25.0%, respectively). The rate of embryonic implantation in the IVF-ET patients was 11.0%, which was significantly higher than that of control embryos (3.7%). CONCLUSION(S) These results implied that IVF-ET, combined with assisted hatching, may improve the PR and implantation rate in patients with repeated IVF failures, but the same was not true in the case of IVF-TET.

Increase in the expression of killer cell inhibitory receptors on peritoneal natural killer cells in women with endometriosis

OBJECTIVE Malfunction of peritoneal natural killer cells (NK) may result in endometriosis. The present study was designed to determine whether the decrease in NK cytotoxicity occurs at early and advanced stages of endometriosis and is due to the increase in the NK inhibition receptors. DESIGN A case control study. SETTING A tertiary-care infertility center . PATIENT(S) A total of 44 women (controls, n = 11; women with early-stage endometriosis, n = 11; and women with advanced-stage endometriosis, n = 22) were included in this study. INTERVENTION(S) Laparoscopic examination. MAIN OUTCOME MEASURE(S) NK cytotoxicity was determined by assay of (51)Cr release against K562 cells, and the expression of killer cell inhibitory receptors (KIR, including NKB1, GL183, and EB6) in NK cells was examined by flow cytometry. RESULT(S) Women with endometriosis showed a decrease in peritoneal NK cytotoxicities against K562 at early and advanced stages of endometriosis. The expression of KIR (NKB1 and EB6) was significantly elevated in the peritoneal NK cells of women with advanced-stage endometriosis compared with controls. KIR (NKB1) was also significantly increased in peritoneal NK cells of women with advanced-stage endometriosis, compared with those of women with early-stage endometriosis. CONCLUSION(S) The results of this study suggest that the decrease in peritoneal NK cytotoxicities against K562 is observed and that this disease may be partially due to the increased expression of KIR on these NK cells.

Increase in the Production of Interleukin-10 Early After Implantation is Related to the Success of Pregnancy

PROBLEM: To study the correlation of interleukin (IL)‐10, IL‐11 leukemia inhibitory factor (LIF), placental growth factor (PlGF), and transforming growth factor (TGF)‐β and outcome of human pregnancy.
 METHOD OF STUDY: We prospectively measured the serum levels of these cytokines in patients undergoing in vitro fertilization (IVF) programs. A total of 60 women (non‐pregnant, n=27; early abortions, n=12; normal pregnancies, n=21) were enrolled.
 RESULTS: There was no difference in the cytokines studied on D0 and D14 among the three groups of women. The increase in PlGF from D0 to D14 after human chorionic gonadotropin (hCG) injection was greater in pregnant women than in non‐pregnant women; however, the difference did not reach significance (P=0.068). The increase in IL‐10 production from D14 to D21 was significant in women with successful pregnancies compared to women in the abortion group.
 CONCLUSIONS: This increase in IL‐10 may be important in sustaining a normal pregnancy early after implantation.

Hormone replacement therapy reverses the decrease in natural killer cytotoxicity but does not reverse the decreases in the T-cell subpopulation or interferon-gamma production in postmenopausal women

OBJECTIVE To investigate the immunologic deviations of postmenopausal women before and after hormone replacement therapy (HRT). DESIGN Prospective study. SETTING University teaching hospital. PATIENT(S) Seventeen postmenopausal women (study group) and 17 women of reproductive age (control group). INTERVENTION(S) Continuous usage of E(2) valerate 2 mg/d and medroxyprogesterone acetate 5 mg/d in postmenopausal women in the study group. MAIN OUTCOME MEASURE(S) Immunophenotyping with flow cytometry, cytokine production with and without mitogen stimulation of the peripheral mononuclear cells, and a natural killer (NK) cell cytotoxicity test against K562 target cells by the (51)Cr-release assay were performed in the control group and in the study group before, 1 month after, and 6 months after HRT. RESULT(S) NK cytotoxicity, interferon-gamma production, and the T-cell subpopulation were significantly decreased, and the subpopulations of CD3(+)CD25(+) and CD3(+)HLA-DR(+) were increased in the study group before HRT when compared with those in the control group. After HRT was given for 6 months, however, the NK cytotoxicity increased significantly in the postmenopausal women to a value similar to that of the control group. CONCLUSION(S) Women after menopause are prone to impaired immune responses. Nevertheless, some of the impairment can be restored after HRT.

Prognostic importance of serial cytokine changes in ascites and pleural effusion in women with severe ovarian hyperstimulation syndrome

OBJECTIVE To determine the prognostic value of various cytokine levels in ascites and pleural effusion during the evolution of severe ovarian hyperstimulation syndrome (OHSS). DESIGN A longitudinal study. SETTING University teaching hospital. PATIENT(S) Twenty patients with severe OHSS who required either paracentesis or thoracentesis or both from whom ascites (n = 56) or pleural effusion (n = 12) samples were obtained. Control peritoneal fluid was obtained from 20 patients undergoing ovarian stimulation for IVF. INTERVENTION(S) Abdominal paracentesis for tense ascites and thoracentesis for massive pleural effusion. Control peritoneal fluid was obtained before oocyte retrieval. MAIN OUTCOME MEASURE(S) Levels of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF), E2, and progesterone concentrations in ascites and pleural effusion. RESULT(S) Levels of VEGF and IL-6 in ascites dropped significantly during the course of OHSS and were not correlated with E2 concentrations. Levels of VEGF were significantly correlated with levels of IL-1 beta, IL-8, and TNF-alpha, as well as progesterone concentrations, hematocrit, and white blood cell counts. None of the cytokine levels measured in pleural effusion were correlated with the course of OHSS. CONCLUSION(S) These results suggest that local cytokines might be involved in the evolution of severe OHSS and possibly serve as prognostic markers for this syndrome.

Increase in the production of interleukin-6, interleukin-10, and interleukin-12 by lipopolysaccharide-stimulated peritoneal macrophages from women with endometriosis.

PROBLEM: To verify whether the peritonea] macrophage (PM) is activated in endometriosis.