Xinmei Zhang

Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids

OBJECTIVE To determine whether nerve fibers can be detected in the endometrium and myometrium in women with painful uterine fibroids and adenomyosis. DESIGN A retrospective immunohistochemical study. SETTING An academic training hospital. PATIENT(S) Thirty-seven women with uterine fibroids and 29 women with adenomyosis. INTERVENTION(S) Histologic sections of contiguous endometrial and myometrial tissues were stained immunohistochemically using the highly specific polyclonal rabbit antiprotein gene product 9.5 (PGP9.5) and monoclonal mouse antineurofilament protein (NF). MAIN OUTCOME MEASURE(S) Results were determined through immunohistochemical staining using PGP9.5 and NF. RESULT(S) We detected PGP9.5-immunoactive nerve fibers in the functional layer of the endometrium in women with pain but not in women without pain. PGP9.5-immunoactive nerve fiber density in the basal layer of the endometrium or myometrium significantly increased in women with pain, however, PGP9.5-immunoactive nerve fiber density had no statistical differences between women with adenomyosis and uterine fibroids. We identified NF-immunoactive nerve fibers in the basal layer of the endometrium and myometrium in women with adenomyosis and uterine fibroids, but found no significant differences. CONCLUSION(S) These results suggest that PGP9.5-immunoactive nerve fibers appearing in the endometrium and myometrium of women with painful adenomyosis and uterine fibroids may play a role in pain generation in these two disorders.

Nerve fibres in ovarian endometriotic lesions in women with ovarian endometriosis

BACKGROUND Although nerve fibres are present in eutopic and ectopic endometrium, it is unclear whether they appear in ovarian endometriotic lesions. We investigated the presence of nerve fibres in ovarian endometriotic lesions and its correlation with clinical parameters in women with ovarian endometriosis. METHODS Histological sections of ovarian endometriotic lesions from 61 women with ovarian endometriosis (Stages II-IV) who underwent laparoscopic endometrioma cystectomy were stained immunohistochemically using a specific polyclonal rabbit anti-protein gene product 9.5 (PGP9.5) antibody to demonstrate myelinated and unmyelinated nerve fibres. RESULTS Nerve fibres stained with PGP9.5 were detected in ovarian endometriotic lesions in 31.1% of women, and most appeared in fibrotic interstitium of ovarian endometriotic lesions. The density of PGP9.5-immunoactive fibres in ovarian endometriotic lesions in women with pain symptoms (n = 35) was higher than in women with no pain symptoms (n = 26, P = 0.039), although the percentage (positive cases/total) of PGP9.5-positive fibres did not differ. In women with pain symptoms, PGP9.5-positive fibres appeared in 40.0% of cases and the density of PGP9.5-immunoactive fibres in ovarian endometriotic lesions was correlated with severity of pain symptoms (r = 0.466, P = 0.005). In women with no pain, PGP9.5-positive fibres were detected in only 5 (19.2%) women. Both the percentage and the density of PGP9.5-positive fibres in ovarian endometriotic lesions were associated with pelvic adhesions (chi2 = 6.833, P = 0.009; Z = 2.442, P = 0.015, respectively) but not with disease severity. CONCLUSIONS PGP9.5-immunoactive nerve fibres in ovarian endometriotic lesions may be involved in the pathophysiology of pain generation and pelvic adhesion formation in women with ovarian endometriosis.

Gene therapy of endometriosis introduced by polymeric micelles with glycolipid-like structure.

To reduce the side effects and improve the lack of clinical treatment countermeasures in endometriosis chemotherapy, a polymeric micelle gene delivery system composed of lipid grafted chitosan micelles (CSO-SA) and the pigment epithelium derived factor (PEDF) was designed. Due to the cationic property, the glycolipid-like micelles could compact the PEDF to form complexes nanoparticles. The complexes nanoparticles with an N/P at 9.6 had 135.6 nm volume average hydrodynamic diameters with a narrow size distribution, and 6.4 ± 0.1 mV surface potential. PEDF can be distributed to endometriotic lesions in a rat model of peritoneal endometriosis mediated by CSO-SA via the intravenous injection. It showed that the CSO-SA/PEDF nanoparticles gene therapy caused decrease in the sizes of the endometriotic lesions and atrophy and degeneration of ectopic endometrium significantly. And it showed no toxicity to the reproductive organs under electron microscope observation. In addition, a reduction in microvessel density labeled by Von Willebrand factor was observed and no decrease in α-Smooth Muscle Actine-positive mature vessels. And the index of apoptotic was increased significantly in endometriotic lesions of CSO-SA/PEDF group. So, glycolipid-like structure micelles mediated PEDF gene delivery system could be used as an effective treatment approach for endometriosis disease.

Reduced Levels of Serum Pigment Epithelium-Derived Factor in Women With Endometriosis:

The authors previously demonstrated decreased levels of pigment epithelium-derived factor (PEDF) in peritoneal fluid of women with endometriosis compared to women without endometriosis. Here, the authors determine whether women with endometriosis have altered levels of PEDF in serum. Peripheral blood samples were collected from 71 women with and without endometriosis (n = 43 and 28, respectively) before laparoscopic surgery. Concentrations of serum PEDF were measured by enzyme-linked immunosorbent assay. We detected lower levels of serum PEDF in women with endometriosis (16.3 ± 6.6 ng/mL) than in those without endometriosis (24.5 ± 7.3 ng/mL; P < .001). In women with endometriosis, the concentrations of serum PEDF were significantly lower in women with pain (n = 11, 12.6 ± 7.1 ng/mL) compared to women without pain (n = 32, 17.5 ± 6.0 ng/mL; P < .05). However, the concentrations of serum PEDF did not correlate with disease stage or site or infertility. In addition, the concentrations of serum PEDF did not show any difference in the phase of the cycle in either group. Our results suggest that reduced levels of serum PEDF in women with endometriosis and disease-related pain may play a role in the pathogenesis of this disease.

Decreased expression of pigment epithelium-derived factor and increased microvascular density in ovarian endometriotic lesions in women with endometriosis

OBJECTIVES To determine whether women with endometriosis have altered expression of pigment epithelium-derived factor (PEDF) in ovarian endometriotic lesions as compared to women without endometriosis. STUDY DESIGN Ectopic and eutopic and normal endometrial tissues were sampled from 40 women with ovarian endometriosis and 20 control women, respectively. Endometrial PEDF expression and microvascular density (MVD) using an antibody to von Willebrand factor (vWF) and alpha-smooth muscle actin (α-SMA) were evaluated by using immunohistochemical staining. RESULTS We detected decreased PEDF expression and increased MVD using anti-vWF and -α-SMA in ovarian endometriotic lesions in women with endometriosis compared with the control group. In women with endometriosis, the MVD using anti-vWF and -α-SMA but not PEDF expression in ovarian endometriotic lesions correlated with the size of ovarian endometriotic cysts and the severity of the disease. Moreover, the MVD using anti-vWF was negatively correlated with PEDF expression in control endometrium but not in ovarian endometriotic lesions. CONCLUSIONS Our results suggest that decreased PEDF expression and increased MVD in ovarian endometriotic lesions might play an important role in the pathogenesis of ovarian endometriosis.

Evaluation of the efficacy of a danazol-loaded intrauterine contraceptive device on adenomyosis in an ICR mouse model

BACKGROUND Danazol, a synthetic steroid with antigonadotrophic properties, has been widely used for the treatment of endometriosis and adenomyosis. However, the local application of danazol to the uterus to treat adenomyosis is controversial. The objective of this study is to develop an effective treatment for adenomyosis using danazol via intrauterine contraceptive device (IUCD) delivery. METHODS An adenomyosis animal model was established using Institute for Cancer Research, Swiss-derived (ICR) mice, grafted with a single pituitary gland (n = 30). Four months after grafting, IUCDs with three different quantities of danazol were prepared and used to treat the ICR mice with adenomyosis. After 2 months of treatment with a danazol-loaded IUCD, the number of adenomyosis nodules and the hematoxylin-eosin staining scores were measured and compared with mice given daily oral danazol and controls (no adenomyosis). RESULTS As the danazol dose increased, the nodule number decreased reaching significance at a dose of 2.0 mg per 20 g body weight (P = 0.002). When compared with oral administration, the plasma danazol concentrations with IUCD delivery were low and stable. CONCLUSIONS These results suggest that an IUCD loaded with an appropriate dose of danazol may be an effective treatment for adenomyosis and that human trials are warranted.

Decreased concentrations of pigment epithelium–derived factor in peritoneal fluid of patients with endometriosis

To determine whether patients with endometriosis have altered levels of pigment epithelium-derived factor (PEDF) in peritoneal fluid, concentrations of PEDF in peritoneal fluid collected from 42 patients with endometriosis and 30 patients without endometriosis were measured with enzyme-linked immunosorbent assay. We detected significantly lower levels of peritoneal fluid PEDF in patients with endometriosis compared with patients without endometriosis, suggesting that peritoneal fluid PEDF plays a role in the pathogenesis of this disorder.

Elevated immunoreactivity of RANTES and CCR1 correlate with the severity of stages and dysmenorrhea in women with deep infiltrating endometriosis

Deep infiltrating endometriosis (DIE) is typically characterized by multifocal locations. It has been shown that CCR1, combined highly with RANTES, contributes to the enhanced recruitment of inflammatory cells at endometriotic sites. As an estrogen-dependent disorder, estrogen receptors are also crucial to the growth of endometriotic tissues. In this study we report the immunohistochemical analysis of RANTES, CCR1, ER-α and ER-β in 48 histological lesions prepared from women with DIE undergoing surgery. Immunohistochemical analysis of RANTES, CCR1, ER-α and ER-β was conducted at different sites of DIE lesions. RANTES was immunolocalized in the cytoplasm and CCR1 in cytomembranes of endometriotic cells. ER-α and ER-β extensively immunostained the nuclei of endometrial glandular, and stromal cells. Immunoreactivity in DIE lesions, similar to the widespread ERs, showed higher expression of RANTES and CCR1 in three types of DIE lesions. There was a significant correlation, independent of cyclic changes, between the expression of RANTES/CCR1 and DIE lesions. RANTES/CCR1 increased significantly according to the severity of dysmenorrhea. RANTES and CCR1 together may provide a potential biomarker for DIE-related pain and inflammatory response in endometriotic lesions of patients with DIE.

Pigment epithelial-derived factor expression in endometriotic lesions in a rat model of endometriosis

Angiogenesis is a prerequisite for endometriotic lesion formation and development. Pigment epithelium-derived factor (PEDF) is a potential inhibitor of angiogenesis. The objective of this study was to detect PEDF immunolocalization in endometriotic lesions and the correlation with vascular endothelial growth factor (VEGF) and microvascular density (MVD) in a rat model of endometriosis. A subcutaneous endometriosis rat model was established by using auto-transplantation. Expression of PEDF, VEGF and MVD labeled by von Willebrand factor (v-WF) in endometriotic lesions and endometrial tissues was evaluated using immunohistochemical staining. We detected lower PEDF immunostaining and higher VEGF and MVD immunostaining in active lesions in a rat model of endometriosis than that in endometriosis endometrium or control endometrium (P<0.05), but no differences between endometriosis and control endometrium were found (P>0.05). In lesions, PEDF expression was negatively correlated with VEGF expression, MVD or sizes of cysts (P<0.01). On the contrary, both VEGF expression and MVD were positively correlated with lesion sizes (P<0.05). In addition, VEGF expression was positively correlated with MVD (P<0.01). Our results suggest that PEDF might be involved in the pathogenesis of endometriosis and may lead to novel treatment for this disease.

Is nerve-sparing surgery suitable for deeply infiltrating endometriosis?

OBJECTIVE To investigate the efficacy of nerve-sparing surgery for deeply infiltrating endometriosis (DIE) and the bladder and sexual dysfunction that follow this procedure. STUDY DESIGN A total of 108 women with DIE underwent conventional surgery (group A, n=63) and nerve-sparing surgery (group B, n=45). Three validated interview-based questionnaires - the visual analogue scale (VAS), the international prostate score symptom (IPSS), and the female sexual function index (FSFI) - were used to evaluate the efficacy and associated complications. RESULTS The VAS scores significantly decreased in both groups A and B after surgery, although two patients (4.4%) in group B had no improvement in their pain symptoms. The total FSFI and each domain scores significantly increased in the two groups after surgery except for satisfaction at the 24-month follow up in group A. Nine patients (15.9%) in group A required self-catheterization postoperatively. Based on the IPSS scores, a significant alteration in voiding symptoms in group A was observed at 6 months but not at 12 months or 24 months after surgery. In group B, however, no significant difference or self-catheterization requirement was observed after surgery. CONCLUSIONS Reduced bladder and sexual dysfunction, but with a risk of absence of pain relief, suggests that the pros and cons of nerve-sparing surgery for DIE should carefully be evaluated before operation.