Huiying Zhang

Insulin resistance: A significant risk factor of endometrial cancer

OBJECTIVE To review the role played by insulin resistance in the development of endometrial cancer. METHODS Relevant manuscripts and studies were searched on Medline using the terms endometrial cancer, insulin resistance, obesity, adipokine, C-peptide, leptin, adiponectin, plasminogen activator inhibitor-1, insulin, PI3K/Akt, Ras/MAPK and metformin alone or in combination. RESULTS Epidemiological studies have shown that insulin resistance is an important potential risk factor of endometrial cancer, and several research studies have been undertaken to determine the mechanism underlying its link to this malignant disease. Risk factors of insulin resistance, such as the inflammatory mediators, adipokines adiponectin, leptin and plasminogen activator inhibitor-1 and excessive androgen are also risk factors of endometrial cancer. High levels of insulin induced by insulin resistance have been found to exert direct and indirect effects that contribute to the development of endometrial cancer. Insulin directly promotes cell proliferation and survival through the PI3K/Akt and Ras/MAPK pathways. Moreover, the network among insulin, estrogen and insulin-like growth factor-1 also contributes to the development of endometrial cancer. Indirectly, insulin leads to changes in sex hormone levels, including increases in the levels of estrogen. Additionally, a small number of studies suggested that metformin, an insulin-sensitizing agent, has therapeutic potential for endometrial cancer. CONCLUSIONS This evidence suggests that insulin resistance plays a central role in endometrial cancer development. Understanding the relationship between insulin resistance and endometrial cancer may supply new ideas to fight this malignancy. Furthermore, combating insulin resistance may be a useful preventive and therapeutic strategy for endometrial cancer.

Visfatin, a potential biomarker and prognostic factor for endometrial cancer

OBJECTIVE Visfatin, a newly discovered adipocytokine, is thought to play a role in the pathogenesis of metabolic-syndrome-related cancers. The aim of this study was to assess the clinical significance of serum levels and tissue expression of visfatin in relation to endometrial cancer (EC). METHODS A total of 234 EC patients were included in this study. Serum visfatin, metabolic and anthropometric parameters were measured in EC patients and controls. Serum visfatin levels were detected using ELISA. Tissue expression of visfatin was analyzed using immunohistochemistry in tissue microarrays. The correlation between clinicopathological variables and visfatin in EC tissues and the prognostic value of visfatin for overall survival was evaluated. RESULTS Serum levels of visfatin were significantly higher in EC patients than in controls (P<0.05). In univariate and multivariate logistic regression models, a positive association between EC and serum visfatin, BMI, waist-to-hip ratio, diabetes, and hypertension was evident (P<0.05). Visfatin expression was significantly higher in EC tissue than in normal endometrial tissue (P=0.001). Moreover, serum visfatin levels were significantly positively correlated with tissue expression of visfatin in EC patients (P<0.05). High visfatin expression in EC tissues was significantly associated with advanced FIGO stage (P=0.016) and myometrial invasion ≥1/2 (P=0.023). The overall survival rate of EC patients was significantly higher in the group with negative visfatin expression than with positive visfatin expression (P=0.035). CONCLUSIONS Visfatin is a potential serum biomarker and prognostic factor for EC that may indicate high risk for EC and EC progression. It may also be a novel potential therapeutic target for EC.

Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent

OBJECTIVE To determine serum insulin levels, expression and phosphorylation of InsR, IRS-1 and Akt in endometrial cancer (EC) tissues, and to explore the correlation between them. To investigate if insulin-induced mitogenic and anti-apoptotic effects are PI3K-dependent in EC cells. METHODS Serum insulin levels were measured by radioimmunoassay. We performed RT-PCR and western blotting to evaluate the expression and activation of key proteins of PI3K/Akt pathway in 63 EC tissues. The proliferation and apoptosis rates were determined with MTT, BrdU and annexin V/PI assays. RESULTS Serum insulin levels and InsR, IRS-1 and Akt expression and phosphorylation were significantly elevated in patients with EC compared to those without EC. Additionally, levels of p-InsR, p-IRS-1, and p-Akt were significantly higher in patients with high-grade, advanced stage, deep myometrial invasion, and lymph-node metastasis. The expression and activation of InsR, IRS-1, and p-Akt were positively related with the levels of serum insulin. The insulin-induced mitogenic and anti-apoptotic effects in EC cells were blocked when cells were pre-incubated with LY294002. Ishikawa 3-H-12 cells showed increased p-Akt levels after treatment with insulin at 10(-8)M for 15min. The insulin-induced Akt activation was inhibited by LY294002 in a dose-dependent manner. CONCLUSION Insulin played an essential role in EC tumorigenesis. Activation of InsR, IRS-1, and Akt was associated with features of aggressive EC. Insulin was a mitogenic and anti-apoptotic agent for EC cells, and these effects were dependent on PI3K/Akt pathway. Decreasing insulin level and blocking the InsR-IRS-PI3K-Akt pathway could be viable preventive and therapeutic strategies for EC.

Diagnostic and therapeutic advancements for aerobic vaginitis

BackgroundAerobic vaginitis (AV) is a newly defined clinical entity that is distinct from candidiasis, trichomoniasis and bacterial vaginosis (BV). Because of the poor recognition of AV, this condition can lead to treatment failures and is associated with severe complications, such as pelvic inflammatory disease, infertility, preterm birth and foetal infections.ObjectiveThis review describes the diagnosis and treatment of AV and the relationship between AV and pregnancy.ResultsThe characteristics of AV include severely depressed levels of lactobacilli, increased levels of aerobic bacteria and an inflamed vagina. The diagnosis is made by microscopy on wet mounts of fresh vaginal fluid, and some distinct clinical features are recognized. Vaginal suppositories that contain kanamycin or clindamycin have shown curative effects in nonpregnant women. Additionally, the application of topical probiotics can restore the vaginal flora and reduce the recurrence of AV. Clindamycin vaginal suppositories and probiotics may be a better choice for gravida with AV than metronidazole. AV requires prompt attention, and the early diagnosis and treatment of AV during pregnancy significantly improves perinatal outcomes.ConclusionFurther research is needed to define the pathogenesis, diagnostic criteria and standard treatment guidelines for AV.

Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway

The involvement of insulin in endometrial carcinoma (EC) was investigated using radioimmunoassay, Western blot, immunoprecipitation, MTT, and Annexin V-FITC/PI assays in tissue samples and cultured cells. Serum levels of insulin, p-p52Shc, p-p46Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1 were elevated in patients with EC. Expression of key proteins in the MEK/ERK pathway, including p-p52Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1, was significantly higher in patients with advanced FIGO stage, high grade, and lymph-node metastasis and correlated positively with serum insulin concentration. Insulin promotes Ishikawa 3-H-12 cell proliferation, survival, and invasion, and these effects induced by insulin were significantly blocked by MEK inhibitor PD98059. Insulin thus promotes EC cell proliferation, survival, and invasion via the MEK/ERK pathway.

Pure nongestational uterine choriocarcinoma in a postmenopausal Chinese woman confirmed with short tandem repeat analysis

Nongestational choriocarcinomas have been observed in the ovaries but rarely the uterus in postmenopausal women. Choriocarcinomas of gestational and nongestational origin have distinct prognoses but cannot be distinguished with routine histologic examination. We report a case of nongestational uterine choriocarcinoma in a 62-year-old Chinese woman that was confirmed with short tandem repeat analysis.

Van Wyk and Grumbach syndrome: two case reports and review of the published work.

Van Wyk and Grumbach syndrome is characterized by a long‐standing history of hypothyroidism, high levels of thyroid‐stimulating hormone, uni‐ or bilateral ovarian cysts, isosexual precocity and a delayed bone age. All of the features can be reversed with treatment of the underlying hypothyroidism. Here, we describe two cases of Van Wyk and Grumbach syndrome presenting with bilateral multicystic ovaries and enlargement of the pituitary gland. One patient suffered from ovarian cyst and hypophysoma resection, the other patient promptly responded to L‐thyroxine with complete regression of the ovarian cyst and other symptoms.

Androgen insensitivity syndrome with gynandroblastoma and vulvar leiomyoma: case report and literature review.

Objective This study aimed to describe a rare case of androgen insensitivity syndrome (AIS) in association with gynandroblastoma and vulvar leiomyomata. Materials and Methods The patient was a 64-year-old phenotypically female person with 46 XY chromosomal karyotypes who presented with a chief complaint of abdominal distension of 1-month duration. She had 2 vulvar masses for more than 20 years and had experienced life-long (untreated) amenorrhea. History and physical examination findings showed the patient to be 175 cm in height, with normal breast development, and a lack of pubic or axillary hair. Serum levels were as follows: testosterone, 1,980 ng/dL; estradiol, 1,380.8 pg/mL. Results In combination with clinical findings, a diagnosis of complete AIS was made. The patient subsequently underwent surgery, during which the bilateral vulvar masses and the rudimentary uterus, right sex gland, and left side of the tumor were resected. Histological examination of the tumor revealed a mass composed primarily of juvenile-type granulosa cells, admixed with a Sertoli cell component that comprised less than 50% of the tumor. The right side of the gonad had an ovarian-like cortex and was considered to be an undeveloped ovary. The left and right side of the vulvar masses were diagnosed with leiomyomas. Conclusions Patients with AIS should be monitored closely because these patients may also experience gonadal tumors. When confronted with gynandroblastoma, close attention should be paid to the patient’s endocrinologic status, and comprehensive endocrinologic analyses should be conducted to make correct treatment decisions.

Endometrial cancer with congenital uterine anomalies: 3 case reports and a literature review

ABSTRACT Background: Uterine malformation is a rare deformity in woman, and only a few cases concerning endometrial cancer arising in patients with congenital uterine anomalies have been reported. Herein, we present 3 cases of endometrial cancer with different congenital uterine anomalies, and review studies involving congenital uterine anomalies associated with endometrial cancer in the past 25 years, to identify similarities and differences in clinicopathologic characteristics and prognosis between endometrial cancer associated with uterine anomalies, and normal uterus. Cases: Case 1 was a 75-year-old gravida 1, para 0, woman with carcinosarcoma (mixed well-differentiated endometrial adenocarcinoma and undifferentiated sarcoma) of the right cavity (grade III, and at least stage II ) of a uterus didelphys. The tumor recurred within 7 months after surgery, salvage radiotherapy was unsuccessful; the patient died 8 months after the surgery. Case 2 was a 63-year-old gravida 5, para 3, woman with a bicornuate uterus and uterus papillary serous carcinoma of the right horn (grade III, stage IIIC). She did not respond to the chemotherapy post surgery and died within 4 months. Case 3 was a 60-year-old gravida 0, para 0, woman with a complete septate uterus and an oblique vaginal septum of the upper region of the vagina with endometrioid adenocarchcinoma of the left cavity (grade II, stage IA). No adjuvant therapy was administered and the patient had recovered 2 y after the surgery. Conclusion: Clinicians should be aware of the coexistence of uterine malignancies and uterine anomalies in patients presenting with persistent abnormal uterine bleeding, but with negative endometrial biopsy or failed in the operation of endometrial biopsy. In such cases, magnetic resonance imaging has an important role in the diagnosis of both malformation and malignancy, and an exploratory laparotomy should be performed to avoid delaying the diagnosis and treatment of cancers.