Effects of 17ß-Estradiol on the Plasminogen Activator System in Vascular Smooth Muscle Cells Treated with Lysophophatidylcholine.

OBJECTIVES: When administered soon after menopause, hormone therapy can prevent coronary heart diseases in women. To explore the mechanism underlying the cardioprotective actions of estrogen, we investigated the effects of 17ß-estradiol (17ß-E2) on the plasminogen activator system using cultured vascular smooth muscle cells (VSMCs). METHODS: VSMCs were isolated from rat aortas. Protein expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated using Western blotting and enzyme-linked immunosorbent assay, respectively. The enzyme activity of PAI-1 in a conditioned medium was assessed via reverse fibrin overlay zymography and that of t-PA was assessed via fibrin overlay zymography. Gene expression was quantified using real-time reverse transcription-polymerase chain reaction. RESULTS: Following pre-treatment for 24 hours, 17ß-E2 suppressed both protein expression and enzyme activity of PAI-1 stimulated by lysophosphatidylcholine (lysoPC) in a significant and dose-dependent manner at a near physiological concentration. Moreover, 17ß-E2 (10⁻7 M) inhibited PAI-1 gene expression, and ICI 182,780-a specific estrogen receptor antagonist-blocked the effects of 17ß-E2 on the PAI-1 protein. 17ß-E2 did not affect t-PA secretion but significantly enhanced free t-PA activity through reduced binding to PAI-1. Furthermore, 17ß-E2 suppressed intracellular reactive oxygen species production and nuclear factor-κB-mediated transcription. CONCLUSIONS: In VSMCs stimulated with lysoPC, 17ß-E2 reduced PAI-1 expression through a non-receptor-mediated mechanism via antioxidant activity as well as a receptor-mediated mechanism; however, it did not alter t-PA secretion. Of note, 17ß-E2 suppressed PAI-1 activity and concurrently enhanced t-PA activity, suggesting a beneficial influence on fibrinolysis.

Differences in risk for type 1 and type 2 ovarian cancer in a large cancer screening trial.

OBJECTIVE: To investigate the role of previous gynecologic surgery, hormone use, and use of non-steroidal anti-inflammatory drugs on the risk of type 1 and type 2 ovarian cancer. METHODS: We utilized data collected for the Prostate, Lung, Colorectal, and Ovarian cancer screening trial. All diagnosed ovarian cancers were divided into three groups: type 1, endometrioid, clear cell, mucinous, low grade serous, and low grade adenocarcinoma/not otherwise specified (NOS); type 2, high grade serous, undifferentiated, carcinosarcoma, and high grade adenocarcinoma/NOS; and other: adenocarcinoma with grade or histology not specified, borderline tumors, granulosa cell tumors. The odds ratios for type 1, type 2, and other ovarian cancers were assessed with regard to historical information for specific risk factors. RESULTS: Ibuprofen use was associated with a decrease in risk for type 1 ovarian cancer. Tubal ligation and oral contraceptive use were associated with a decrease in risk for type 2 ovarian cancer. A history of ectopic pregnancy was associated with a decreased risk for all ovarian cancers by almost 70%. CONCLUSION: These findings support the hypothesis that carcinogenic pathways for type 1 and type 2 ovarian cancer are different and distinct. The marked reduction in all ovarian cancer risk noted with a history of ectopic pregnancy and salpingectomy implies that the fallopian tube plays a key role in carcinogenesis for both type 1 and type 2 ovarian cancer.

Ovarian cancer screening in menopausal females with a family history of breast or ovarian cancer.

OBJECTIVE: To determine whether annual screening reduces ovarian cancer mortality in women with a family history of breast or ovarian cancer. METHODS: Data was obtained from the Prostate, Lung, Colorectal, and Ovarian cancer trial, a randomized multi-center trial conducted to determine if screening could reduce mortality in these cancers. The trial enrolled 78,216 women, randomized into either a screening arm with annual serum cancer antigen 125 and pelvic ultrasounds, or usual care arm. This study identified a subgroup that reported a first degree relative with breast or ovarian cancer. Analysis was performed to compare overall mortality and disease specific mortality in the screening versus usual care arm. In patients diagnosed with ovarian cancer, stage distribution, and survival were analyzed as a secondary endpoint. RESULTS: There was no significant difference in overall mortality or disease specific mortality between the two arms. Ovarian cancer was diagnosed in 48 patients in the screening arm and 44 patients in the usual care arm. Screened patients were more likely to be diagnosed at an earlier stage than usual care patients. Patients in the screening arm diagnosed with ovarian cancer experienced a significantly improved survival compared to patients in the usual care arm; relative risk 0.66 (95% CI, 0.47 to 0.93). CONCLUSION: Screening did not appear to decrease ovarian cancer mortality in participants with a family history of breast or ovarian cancer. Secondary endpoints, however, showed notable differences. Significantly fewer patients were diagnosed with advanced stage disease in the screening arm; and survival was significantly improved. Further investigation is warranted to assess screening efficacy in women at increased risk.

Third and fourth degree perineal injury after vaginal delivery: does race make a difference?

Severe perineal injury (third and fourth degree laceration) at the time of vaginal delivery increases the risk of fecal incontinence, chronic perineal pain, and dyspareunia.1-5 Studies suggest the prevalence of severe perineal injury may vary by racial group.6 The purpose of the current study was to examine rates of severe perineal injury in different Asian and Pacific Islander subgroups. A retrospective cohort study was performed among all patients who had a vaginal delivery at Queens Medical Center in Honolulu, Hawai'i between January 1, 2002 and December 31, 2003. Demographic and health related variables were obtained for each participant. Maternal race/ethnicity (Japanese, Filipino, Chinese, other Asian, Part-Hawaiian/Hawaiian, Micronesian, other Pacific Islander, Caucasian, multiracial [non-Hawaiian], and other) was self-reported by the patient at the time admission. The significance of associations between racial/ethnic groups and demographic and health related variables was determined using chi-square tests for categorical variables and analysis of variance for continuous factors. Multiple logistic regression was performed to adjust for potential confounders when examining severe laceration rates. A total of 1842 subjects met inclusion criteria. The proportion of severe perineal lacerations did not differ significantly between racial groups. In the multiple logistic regression analysis, operative vaginal delivery was related to both race and severe perineal laceration. However, despite adjusting for this variable, race was not associated with an increased risk of having a severe laceration (P = .70). The results of this study indicate the risk of severe perineal laceration does not differ based on maternal race/ethnicity.

Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial.

CONTEXT: Screening for ovarian cancer with cancer antigen 125 (CA-125) and transvaginal ultrasound has an unknown effect on mortality. OBJECTIVE: To evaluate the effect of screening for ovarian cancer on mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of 78,216 women aged 55 to 74 years assigned to undergo either annual screening (n = 39,105) or usual care (n = 39,111) at 10 screening centers across the United States between November 1993 and July 2001. Intervention The intervention group was offered annual screening with CA-125 for 6 years and transvaginal ultrasound for 4 years. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual care group was not offered annual screening with CA-125 for 6 years or transvaginal ultrasound but received their usual medical care. Participants were followed up for a maximum of 13 years (median [range], 12.4 years [10.9-13.0 years]) for cancer diagnoses and death until February 28, 2010. MAIN OUTCOME MEASURES: Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. RESULTS: Ovarian cancer was diagnosed in 212 women (5.7 per 10,000 person-years) in the intervention group and 176 (4.7 per 10,000 person-years) in the usual care group (rate ratio [RR], 1.21; 95% confidence interval [CI], 0.99-1.48). There were 118 deaths caused by ovarian cancer (3.1 per 10,000 person-years) in the intervention group and 100 deaths (2.6 per 10,000 person-years) in the usual care group (mortality RR, 1.18; 95% CI, 0.82-1.71). Of 3285 women with false-positive results, 1080 underwent surgical follow-up; of whom, 163 women experienced at least 1 serious complication (15%). There were 2924 deaths due to other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10,000 person-years) in the intervention group and 2914 deaths (76.2 per 10,000 person-years) in the usual care group (RR, 1.01; 95% CI, 0.96-1.06). CONCLUSIONS: Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications. Trial Registration clinicaltrials.gov Identifier: NCT00002540.

Pathologic findings following false-positive screening tests for ovarian cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial.

OBJECTIVE: In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), ovarian cancer screening with transvaginal ultrasound (TVU) and CA-125 produced a large number of false-positive tests. We examined relationships between histopathologic diagnoses, false-positive test group, and participant and screening test characteristics. METHODS: The PLCO ovarian cancer screening arm included 39,105 women aged 55-74 years assigned to annual CA-125 and TVU. Histopathologic diagnoses from women with false-positive tests and subsequent surgery were reviewed in this analysis: all CA125+ (n=121); all CA125+/TVU+ (n=46); and a random sample of TVU+ (n=373). Demographic and ovarian cancer risk factor data were self-reported. Pathologic diagnoses were abstracted from surgical pathology reports. We compared participant characteristics and pathologic diagnoses by category of false-positive using Pearson χ2, Fisher's exact, or Wilcoxon-Mann-Whitney tests. RESULTS: Women with a false-positive TVU were younger (P<0.001), heavier (P<0.001), and reported a higher frequency of prior hysterectomy (P<0.001). Serous cystadenoma, the most common benign ovarian diagnosis, was more frequent among women with TVU+ compared to CA-125+ and CA-125+/TVU+ (P<0.001). Benign non-ovarian findings were commonly associated with all false-positives, although more frequently with CA-125+ than TVU+ or CA-125+/TVU+ groups (P=0.019). Non-ovarian cancers were diagnosed most frequently among CA-125+ (P<0.001). CONCLUSIONS: False-positive ovarian cancer screening tests were associated with a range of histopathologic diagnoses, some of which may be related to patient and screening test characteristics. Further research into the predictors of false-positive ovarian cancer screening tests may aid efforts to reduce false-positive results.

Prevalence, incidence, and natural history of simple ovarian cysts among women >55 years old in a large cancer screening trial.

OBJECTIVE: The purpose of this study was to measure the occurrence and natural history of simple ovarian cysts in a cohort of older women. STUDY DESIGN: Simple cysts were ascertained among a cohort of 15,735 women from the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial through 4 years of transvaginal ultrasound screening. RESULTS: Simple cysts were seen in 14% of women the first time that their ovaries were visualized. The 1-year incidence of new simple cysts was 8%. Among ovaries with 1 simple cyst at the first screen, 54% retained 1 simple cyst, and 32% had no cyst 1 year later. Simple cysts did not increase risk of subsequent invasive ovarian cancer. CONCLUSION: Simple ovarian cysts are fairly common among postmenopausal women, and most cysts appear stable or resolve by the next annual examination. These findings support recent recommendations to follow unilocular simple cysts in postmenopausal women without intervention.

Results from four rounds of ovarian cancer screening in a randomized trial.

OBJECTIVE: To test whether annual screening with transvaginal ultrasonography and CA 125 reduces ovarian cancer mortality. METHODS: Data from the first four annual screens, denoted T0-T3, are reported. A CA 125 value at or above 35 units/mL or an abnormality on transvaginal ultrasonography was considered a positive screen. Diagnostic follow-up of positive screens was performed at the discretion of participants' physicians. Diagnostic procedures and cancers were tracked and verified through medical records. RESULTS: Among 34,261 screening arm women without prior oophorectomy, compliance with screening ranged from 83.1% (T0) to 77.6% (T3). Screen positivity rates declined slightly with transvaginal ultrasonography, from 4.6 at T0 to 2.9-3.4 at T1-T3; CA 125 positivity rates (range 1.4-1.8%) showed no time trend. Eighty-nine invasive ovarian or peritoneal cancers were diagnosed; 60 were screen detected. The positive predictive value (PPV) and cancer yield per 10,000 women screened on the combination of tests were similar across screening rounds (range 1.0-1.3% for PPV and 4.7-6.2 for yield); however, the biopsy (surgery) rate among screen positives decreased from 34% at T0 to 15-20% at T1-T3. The overall ratio of surgeries to screen-detected cancers was 19.5:1. Seventy-two percent of screen-detected cases were late stage (III/IV). CONCLUSION: Through four screening rounds, the ratio of surgeries to screen-detected cancers was high, and most cases were late stage. However, the effect of screening on mortality is as yet unknown. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00002540 LEVEL OF EVIDENCE: II.

The epidemiology of CA-125 in women without evidence of ovarian cancer in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial.

OBJECTIVE: To determine the epidemiology of CA-125 in women without ovarian cancer. METHODS: We analyzed demographic, medical and lifestyle characteristics related to CA-125, measured using the Centocor CA-125II RIA assay, among 25,608 multi-ethnic U.S. women aged 55-74 years enrolled in a cancer screening trial and found to have no evidence of ovarian cancer. RESULTS: Mean CA-125 level was 11.9 U/ml (SD 8.3); median 10.0 U/ml, interquartile range 8.0-14.0. High levels, using the clinical cut point of >or=35 U/ml, were associated with increased age (p<0.001) and former smoking (p<0.021), while hysterectomy and obesity were protective (p<0.001). Mean levels were higher with increasing age (p<0.001), ever use of hormone therapy (p<0.001), former smoking (p<0.017) and history of breast cancer (p<0.002), but lower (p<0.001) with non-White status, previous hysterectomy, current smoking, and obesity. Current hormone therapy use was not associated with CA-125 in women without a uterus. CONCLUSION: In post-menopausal women without ovarian cancer, CA-125 level is influenced by a number of factors, including race/ethnicity, age, hysterectomy, smoking history and obesity.

Treatment of vasomotor symptoms in the menopausal transition and postmenopausally: psychiatric comorbidity.

This article aims to educate the nonpsychiatric as well as the psychiatric clinician on the impact of vasomotor symptoms in women with comorbid psychiatric problems and the challenges of treating vasomotor symptoms in these women. The pathophysiology, prevalence and common risk factors associated with disturbing hot flashes in the menopausal transition are reviewed. Hormonal, nonhormonal and behavioral treatment options of vasomotor symptoms for these women are discussed. Special pharmacokinetic implications for hormonal treatment of those women on anticonvulsant medications for the treatment of their mood disorders, on tamoxifen and/or with high or low sex hormone-binding globulin are examined. An in-depth discussion of mood and the menopausal transition, theoretical mechanisms for mood problems with the symptomatic menopause and the impact of stress on the symptomatic menopause are found elsewhere in this clinical review series on psychiatric illness, stress and the symptomatic menopause.

Hawaii cohort study of serum micronutrient concentrations and clearance of incident oncogenic human papillomavirus infection of the cervix.

The degree to which the resolution of human papillomavirus (HPV) infection parallels exposure to other factors, particularly those related to nutritional status, is a relatively unexplored area of research. We established a cohort of women for long-term follow-up to examine the association of serum retinol, carotenoid, and tocopherol concentrations with the clearance of incident cervical HPV infection. Interviews and biological specimens were obtained at baseline and at 4-month intervals. At each visit, a cervical cell specimen for HPV DNA analysis and cytology and a fasting blood sample to measure micronutrient levels were collected. A Cox proportional hazards model was used to study the relationship between clearance of 189 incident (type-specific) oncogenic HPV infections and the levels of 20 serum micronutrients among 122 women. Higher circulating levels of trans-zeaxanthin, total trans-lutein/zeaxanthin, cryptoxanthin (total and beta), total trans-lycopene and cis-lycopene, carotene (alpha, beta, and total), and total carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (120 days) was not significantly associated with circulating levels of carotenoids or tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.

Anal human papillomavirus infection in women and its relationship with cervical infection.

Human papillomavirus (HPV), the primary cause of cervical cancer, is also associated with the development of anal cancer. Relatively little is known about the epidemiology of anal HPV infection among healthy females and its relationship to cervical infection. We sought to characterize anal HPV infection in a cohort of adult women in Hawaii. Overall, 27% (372 of 1,378) of women were positive for anal HPV DNA at baseline compared with 29% (692 of 2,372) with cervical HPV DNA. Among women with paired anal and cervical samples, anal infection without accompanying cervical infection was observed in 14% (190 of 1,363). Concurrent anal and cervical HPV infections were observed in 13% (178 of 1,363) of women. Women with cervical HPV infection had >3-fold increased risk of concurrent anal infection. Concurrent anal and cervical HPV infection was most prevalent among the youngest women and steadily decreased through age 50 years. By contrast, the prevalence of anal infection alone remained relatively steady in all age groups. Compared with cervical infections, the overall distribution of HPV genotypes in the anus was more heterogeneous and included a greater proportion of nononcogenic types. A high degree of genotype-specific concordance was observed among concurrent anal and cervical infections, indicating a common source of infection. Nevertheless, the association of anal intercourse with anal HPV infection was limited to those women without accompanying cervical infection. The relationship of anal to cervical infection as described in this study has implications for the development of anal malignancies in women.

The role of complementary and alternative medicine in management of menopausal symptoms.

There is a great need for alternatives to hormone therapy for use by symptomatic menopausal women. Alternatives to estrogen can en-compass lifestyle change, complementary and alternative medicine (CAM), and prescription nonhormonal therapies. The use of CAM therapies for menopausal symptoms is widespread and has been increasing. In recent years, there has been an increase in the quantity and quality of research related to CAM therapy use for menopausal symptoms. A highly effective and safe CAM therapy for menopausal symptoms would be valuable but has remained elusive to date. This article reviews randomized controlled trials examining the efficacy of CAM therapies for menopausal symptoms.

Hip fracture prevention in postmenopausal women.

UNLABELLED: Hip fracture is a devastating outcome associated with postmenopausal osteoporosis. This fracture causes considerable pain, disability, diminished quality of life, and mortality. Although bone loss is an important factor associated with hip fracture, there are other demographic and clinical factors such as those that increase the risk of falling (e.g., unsteady gait, medications) that contribute to the likelihood of experiencing a hip fracture. Nonpharmacological interventions to reduce hip fracture risk include regular weight-bearing exercise, fall intervention programs, and external hip protectors. Patients should receive calcium and/or vitamin D supplementation as necessary. Among available pharmacologic options, the bisphosphonates, risedronate (Actonel) and alendronate (Fosamax), have reduced the risk of hip fracture in postmenopausal women with osteoporosis. Raloxifene (Evista), salmon calcitonin nasal spray (Miacalcin), and teriparatide (Forteo) have not demonstrated hip fracture risk reduction in controlled clinical trials. Hormone therapy (HT) reduced hip fracture risk in a recent large placebo-controlled trial; however, the risk/benefit profile of HT has resulted in recommendations to consider alternatives for the management of osteoporosis. Postmenopausal women with osteoporosis should receive adequate calcium/vitamin D supplementation, be encouraged to exercise, and institute risk factor interventions. Treatment with a bisphosphonate should be considered for those who are also at increased risk for hip fracture. TARGET AUDIENCE: Obstetricians & Gynecologyists, Family Physicians LEARNING OBJECTIVES: After completion of this article the reader should be able to list the demographic risk factors for osteoporosis and related fractures, to outline the cost and consequences of hip fractures, and to summarize the various pharmacologic and non-pharmacologic interventions used to reduce the risk of hip fracture.

Local anesthetic reduces the pain of colposcopic biopsies: a randomized trial.

OBJECTIVE: This study was undertaken to determine whether administration of local anesthetic reduces pain associated with colposcopically directed cervical biopsies. STUDY DESIGN: Fifty-six patients undergoing colposcopically directed cervical biopsies were randomly selected prospectively to receive a 1% lidocaine injection or no injection before the biopsy procedure. Pain was assessed by using a 10-cm visual analog scale at various points during the procedure. Data were analyzed with the Student t test. RESULTS: Injection of lidocaine resulted in a reduction in pain scores for cervical biopsies (4.004 to 1.166, P: <.001), endocervical curettage (5.757 to 3.900, P =.0018), and overall procedure scores (4.911 to 3.145, P =.0013). CONCLUSION: This pilot study demonstrates that injection of local anesthetic at the site of colposcopically direct cervical biopsies decreases the pain perceived by patients.

The Association of Plasma Micronutrients with the Risk of Cervical Atypical Squamous Cells of Undetermined Significance (ASCUS).

Little is known about factors that favor the development of cervical atypical squamous cells of undetermined significance (ASCUS), nor how these factors might affect the pathogenesis of cervical neoplasia. The primary focus of this case-control study among the multiethnic population of Hawaii was to identify biomarkers of diet in the recent past that may influence the risk of ASCUS, after carefully accounting for the presence of HPV DNA. Cases included 185 women with ASCUS and 191 cytologically-normal controls diagnosed between 1992 and 1996 from three clinics in Honolulu, Hawaii. In-person interviews were conducted in the subjects' homes, a fasting blood sample was drawn to measure plasma levels of various micronutrients, and the presence and type of HPV was determined in exfoliated cell samples using Polymerase Chain Reaction (PCR) dot blot hybridization. As results, we found an inverse dose-response gradient with increasing plasma concentrations of &mgr;-cryptoxanthin and &mgr;-tocopherol for the development of ASCUS. The odds ratio for ASCUS among women in the highest quartile compared with women in the lowest quartile of total cryptoxanthin was 0.5 (95% confidence interval (CI): 0.3-1.0), &mgr;-cryptoxanthin was 0.4 (0.2-0.8), total tocopherol was 0.5 (0.2-1.0), &mgr;-tocopherol was 0.5 (0.2-1.0), and &mgr;-tocopherol was 0.4 (0.2-0.8). Little association of plasma levels of lutein/zeaxanthin, lycopene, &mgr;- or &mgr;-carotene, retinol, vitamin C, or cholesterol, with disease risk was evident. Our findings suggest that women with high circulating concentrations of cryptoxanthin and tocopherol may be at a reduced risk of ASCUS.

The Association of Plasma Micronutrients with the Risk of Cervical Atypical Squamous Cells of Undetermined Significance (ASCUS).

Little is known about factors that favor the development of cervical atypical squamous cells of undetermined significance (ASCUS), nor how these factors might affect the pathogenesis of cervical neoplasia. The primary focus of this case-control study among the multiethnic population of Hawaii was to identify biomarkers of diet in the recent past that may influence the risk of ASCUS, after carefully accounting for the presence of HPV DNA. Cases included 185 women with ASCUS and 191 cytologically-normal controls diagnosed between 1992 and 1996 from three clinics in Honolulu, Hawaii. In-person interviews were conducted in the subjects' homes, a fasting blood sample was drawn to measure plasma levels of various micronutrients, and the presence and type of HPV was determined in exfoliated cell samples using Polymerase Chain Reaction (PCR) dot blot hybridization. As results, we found an inverse dose-response gradient with increasing plasma concentrations of &mgr;-cryptoxanthin and &mgr;-tocopherol for the development of ASCUS. The odds ratio for ASCUS among women in the highest quartile compared with women in the lowest quartile of total cryptoxanthin was 0.5 (95% confidence interval (CI): 0.3-1.0), &mgr;-cryptoxanthin was 0.4 (0.2-0.8), total tocopherol was 0.5 (0.2-1.0), &mgr;-tocopherol was 0.5 (0.2-1.0), and &mgr;-tocopherol was 0.4 (0.2-0.8). Little association of plasma levels of lutein/zeaxanthin, lycopene, &mgr;- or &mgr;-carotene, retinol, vitamin C, or cholesterol, with disease risk was evident. Our findings suggest that women with high circulating concentrations of cryptoxanthin and tocopherol may be at a reduced risk of ASCUS.