Tasuku Harada

Role of cytokines in endometriosis

OBJECTIVE To review the literature on the role of cytokines in the pathogenesis of endometriosis and endometriosis-associated infertility. DESIGN Pertinent studies were identified by a computer search of MEDLINE. References of selected articles were hand-searched for additional citations. RESULT(S) Recent studies suggest that the peritoneal fluid of women with endometriosis contains an increased number of activated macrophages that secrete various local products, such as growth factors and cytokines. Levels of several cytokines were reported to be elevated in the peritoneal fluid of women with endometriosis. Because the peritoneal environment may be controlled by locally regulated factors, cytokines are believed to play a role in the development and progression of endometriosis and endometriosis-associated infertility. A possible pathogenic mechanism links cytokines with endometriosis. CONCLUSION(S) Cytokines, which are produced by many cell types including endometriotic tissues, play diverse roles in the pathogenesis of endometriosis and endometriosis-associated infertility. More studies about the specific role of these cells and soluble factors are needed to improve understanding of endometriosis and to develop novel therapies.

Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis.

OBJECTIVE Our purpose was to investigate the relationship between the levels of interleukin-6, interleukin-6 soluble receptor, and tumor necrosis factor-alpha in peritoneal fluid and the size and number of active red endometriotic lesions. STUDY DESIGN In a university hospital 39 women of reproductive age underwent either laparoscopy for infertility workup or laparoscopic surgery for ovarian chocolate cysts. Peritoneal fluid was collected by laparoscopy. Active lesions, such as red flamelike lesions, glandlike lesions, and red vesicles, were scored according to the revised American Fertility Society classification system according to the size and number of active lesions. Peritoneal fluid levels of interleukin-6, interleukin-6 soluble receptor, and tumor necrosis factor-alpha levels were determined by enzyme-linked immunosorbent assays. The relationship between peritoneal fluid concentrations of interleukin-6 and tumor necrosis factor-alpha and the score of active endometriosis was investigated. RESULTS Peritoneal fluid levels of interleukin-6 and tumor necrosis factor-alpha were significantly higher in patients with endometriosis compared with patients without endometriosis. The concentrations in patients with active endometriosis increased as the size and the number of active lesions increased. Cyclic variations in interleukin-6 concentrations were seen in peritoneal fluid from patients with endometriosis; the concentrations in the secretary phase were significantly higher than those in the proliferative phase. CONCLUSIONS Increased peritoneal fluid levels of interleukin-6 in patients with active red endometriosis may relate to endometriosis-associated infertility and to the pathogenesis of endometriosis.

Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis—a randomized, double-blind, multicenter, controlled trial

OBJECTIVE To compare the efficacy and safety of dienogest (DNG) with intranasal buserelin acetate (BA) in patients with endometriosis. DESIGN Phase III, randomized, double-blind, multicenter, controlled trial. SETTING Twenty-four study centers in Japan. PATIENT(S) Two hundred seventy-one patients with endometriosis. INTERVENTION(S) Dienogest (2 mg/day, orally) or BA (900 microg/day, intranasally) for 24 weeks. MAIN OUTCOME MEASURE(S) The pre- to posttreatment changes in the scores of five subjective symptoms during nonmenstruation (lower abdominal pain, lumbago, defecation pain, dyspareunia, and pain on internal examination) and two objective findings (induration in the pouch of Douglas and limited uterine mobility). RESULT(S) Dienogest reduced the scores of all symptoms and findings at the end of treatment, and the mean changes in the scores of all symptoms and findings except induration in the pouch of Douglas were comparable to those obtained with BA. Compared with BA, DNG was associated with irregular genital bleeding more frequently and with fewer hot flushes. The reduction in bone mineral density (BMD) during DNG treatment was significantly lower than that during BA treatment. CONCLUSION(S) DNG is as effective as intranasal BA in alleviating endometriosis, and causes less BMD loss.

Diagnostic accuracy of diffusion-weighted imaging in differentiating benign from malignant ovarian lesions.

To clarify the diagnostic accuracy of diffusion‐weighted imaging (DWI) in differentiating benign from malignant ovarian lesions.

Altered gene expression and secretion of interleukin-6 in stromal cells derived from endometriotic tissues

OBJECTIVE To compare the expression of interleukin-6 (IL-6) in endometrial and endometriotic cells. DESIGN Prospective study. SETTING Department of Obstetrics and Gynecology, Tottori University Hospital, Yonago, Japan. PATIENT(S) Twenty patients who underwent either hysterectomy or laparoscopic surgery. INTERVENTION(S) Endometrial and endometriotic stromal cells were obtained from normal endometrium and from chocolate cyst linings of the ovary. Peritoneal macrophages were isolated from peritoneal fluids. Cells were cultured in the presence or absence of tumor necrosis factor-alpha. MAIN OUTCOME MEASURE(S) Gene expression of IL-6 was examined by Northern blot analysis. Interleukin-6 protein production was examined by immunocytochemical staining and ELISA. RESULT(S) A single IL-6 messenger RNA band of approximately 1.3 kilobases was detected in endometriotic stromal cells. Tumor necrosis factor-alpha increased the expression of IL-6 messenger RNA in endometriotic cells in a dose-dependent manner. In endometrial stromal cells, IL-6 messenger RNA signals were much weaker. Endometriotic stromal cells produced significantly larger amounts of IL-6 compared with endometrial stromal cells under basal conditions and after stimulation with tumor necrosis factor-alpha. Interleukin-6 protein was detected in cells isolated from endometriotic tissues by immunocytochemical staining. Interleukin-6 production by cultured macrophages from patients with endometriosis and endometriotic stromal cells was comparable. CONCLUSION(S) Altered gene expression and protein secretion of IL-6 in patients with endometriosis may contribute to the pathogenesis of the disease and/or to endometriosis-associated infertility.

Long-term use of dienogest for the treatment of endometriosis

Aim:  To investigate the safety and efficacy of 52 weeks of dienogest treatment in patients with endometriosis.

Role of Cytokines in Progression of Endometriosis

Peritoneal fluid in women with endometriosis contains an increased number of activated macrophages that secrete a variety of cytokines, including interleukin (IL)-6, IL-8, vascular endothelial growth factor, and tumor necrosis factor-α (TNF-α). Cytokines may be involved in the control of implantation and the growth of endometrial cells outside the uterus. In addition, several cytokines have been implicated in or directly associated with angiogenic activity in endometriosis. There could be a relationship between the levels of cytokines in the peritoneal fluid of patients with endometriosis and the status of the lesions in such patients. Peritoneal endometriosis can be classified as having red, black, or white lesions. Red lesions are known to be an active form of early endometriosis, because vascularization and mitotic activity are shown to be most prominent in these lesions. We found that the peritoneal fluid levels of TNF-α and IL-8 were significantly higher in patients with endometriosis, and correlated with the size and number of active lesions. In addition, TNF-α and IL-8 stimulated the growth of ectopic endometrial stromal cells. These cytokines with angiogenic activity may therefore have significant roles in the pathogenesis of endometriosis.

Role of cytokines in endometriosis-associated infertility.

Endometriosis, which is common in women of reproductive age, may affect fertility. It is also clear that mechanical disruption of the pelvic anatomy may cause infertility. However, our understanding of the association between the early stage of endometriosis and infertility remains incomplete. Bloody peritoneal fluid (PF) is frequently observed in the cul-de-sac of endometriosis patients and contains various biologically active factors. We found that the concentrations of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in PF from patients with endometriosis were significantly higher than that of patients with endometriosis. There were significantly positive correlations between the levels of TNF-α and IL-6. We compared the levels of these cytokines with regard to the R-AFS stages and scores, but no differences were observed. In contrast, these cytokines correlate with the number and extent of red color peritoneal endometriosis. TNF-α increased the expression of IL-6 messenger RNA and protein in endometriotic stromal cells derived from chocolate cyst in a dose-dependent manner. The addition of IL-6 inhibited the development of mouse preimplantation embryo and impaired sperm function. We concluded that increased levels of IL-6 in peritoneal fluid of patients with active red endometriosis might be related to endometriosis-associated fertility.

Apoptosis and endometriosis.

Apoptosis is a distinctive form of programmed cell death resulting in the efficient elimination of cells without eliciting an inflammatory response. Endometriosis is characterized by the presence of endometrial cells with capacity to avoid apoptosis outside the uterus. Apoptosis plays a fundamental role for the pathogenesis of endometriosis. Eutopic endometrium from women with endometriosis has increased expression of anti-apoptotic factor and decreased expression of pro-apoptotic factors compared with endometrium from healthy women. These differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and development of endometriosis. Increased apoptosis of Fas-bearing immune cells in the peritoneal cavity may leads to their decreased scavenger activity that eventually results in prolonged survival of ectopic endometrial cells in women with endometriosis. This study is a current review of the literatures focused on the physiological role of apoptosis in normal endometrium and alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. The role of apoptosis in the treatment of endometriosis is also reviewed.

Infertility treatment : from cookery to science. The epidemiology of randomised controlled trials

Objectives To review the epidemiology of published randomised controlled trials in infertility treatment over the last 25 years, with special emphasis on the number and quality of trials.