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Creasman J.S.,Gynecology and Reproductive science | Creasman J.S.,University of San Francisco | Beattie M.S.,University of San Francisco
JAMA Internal Medicine | Year: 2013

Background: For women at potentially increased risk for ovarian cancer, data regarding screening are limited. Previous studies have reported on the behaviors of BRCA mutation carriers, but less is behaviors of non-BRCA carriers. We surveyed a large cohort of women after BRCA testing to iden and posttest predictors of risk-reducing and screening interventions. Methods: A median of 3.7 years after BRCA testing, 1447 women who received genetic counseling at 2 hospital sites were surveyed, with a 77.6% response rate. We analyzed data from 1077 survey performed univariate and multivariate logistic regression analyses to identify predictors of risk-red oophorectomy (RRSO), screening transvaginal ultrasonography (TVUS), and screening serum can (CA-125). Results: Among the respondents, 201 women (18.7%) received positive test results for a deleteriou women (9.6%) received true-negative results, and 773 women (71.8%) received uninformative resu of eligible women underwent RRSO and 39.6% used screening procedures. A positive BRCA result (odds ratio [OR], 28.1;95% CI, 16.2-48.6), TVUS (9.5 [4.3-21.0]), and serum CA-125 (13.0 [5.5-29 true-negative BRCA result reduced the OR for RRSO (0.1 [0.0-0.6]), TVUS (0.2 [0.1-0.5]), and ser [0.1-0.7]). Of the 71.8% of women who received uninformative results after BRCA testing, 12.3% underwent RRSO, 33.8% reported ever having undergone screening serum CA-125 since BRCA tes reported ever having undergone screening TVUS since BRCA testing. Conclusions: Results of BRCA testing strongly predict RRSO and ovarian cancer screening. Use of ovarian screening was reported in a sizable percentage of non-BRCA carriers despite insufficient the effectiveness of these interventions.


Wang B.,Gynecology and Reproductive science | Parobchak N.,Gynecology and Reproductive science | Rosen M.,Gynecology and Reproductive science | Roche N.,Gynecology and Womens Health | Rosen T.,Gynecology and Reproductive science
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Progesterone (P4)contributes to the maintenance of human pregnancy, in part by inhibiting activity of the human pro-labor genes CRH and cyclooxygenase-2 (COX-2). However, the molecular mechanisms underlying the action of P4 remain poorly defined. We have shown that in human placenta, the constitutively activated noncanonical nuclear factor (NF)-κB pathway positively regulates CRH and COX-2, which is further stimulated by glucocorticoid receptor signaling. Objective: We investigated the role of P4 receptor (PR) in the regulation of nuclear activity of v-rel avian reticuloendotheliosis viral oncogene homolog B (RelB)/NF-κB2 and, in turn, expression of placental CRH and COX-2. Methods: We used a variety of techniques including gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, quantitative RT-PCR, and immunohistochemical staining assays in human placental tissues and primary culture of human cytotrophoblast. Results: We identified PR isoform-A (PR-A) as the only isoform of PR produced in human placenta. PR-A levels were lower in term placenta than in midterm placenta. Depletion of PR-A by short interfering RNA derepressed inhibition of CRH and COX-2 by P4 and the synthetic progestin 17α- hydroxyprogesterone caproate. Overexpression of PR-A inhibited transcription of CRH and COX-2, which was further downregulated by treatment with P4 or 17α-hydroxyprogesterone caproate. Such an inhibition was mediated by a negative functional interaction of PR-A with the activity of RelB/NF-κB2. Conclusion: P4 inhibits the pro-labor genesCRHand COX-2 via PR-A repression of the noncanonical NF-κB signaling in human placenta. Characterization of these pathways may identify potential drug targets for prevention of preterm birth. Copyright © 2014 by the Endocrine Society.


Vintzileos A.M.,Winthrop University | Ananth C.V.,Gynecology and Reproductive science
American Journal of Obstetrics and Gynecology | Year: 2010

Most physicians have had little or no exposure to systematic teaching or training during the medical school and residency with respect to writing and publishing an original research article. The framework of every article should include the study objective(s), study design, results, and conclusion(s). The current "Clinical Opinion" article proposes a set of guidelines, based on the authors' experience, which can be useful to junior physicians who plan to publish their work. These guidelines should assist not only in the writing process of the initial manuscript but also in responding to reviews and in modifying the original manuscript. © 2010 Mosby, Inc. All rights reserved.


Ananth C.V.,Gynecology and Reproductive science | Basso O.,U.S. National Institutes of Health
Epidemiology | Year: 2010

Background: Hypertensive disorders of pregnancy are more frequent in primiparous women, but may be more severe in multiparas. We examined trends in stillbirth and neonatal mortality related to pregnancy-induced hypertension (PIH), and explored whether mortality varied by parity and maternal race. Methods: We carried out a population-based study of 57 million singleton live births and stillbirths (24-46 weeks' gestation) in the United States between 1990 and 2004. We estimated rates and adjusted odds ratios (ORs) of stillbirth and neonatal death in relation to PIH, comparing births in 1990-1991 with 2003-2004. Results: PIH increased from 3.0% in 1990-1991 to 3.8% in 2003-2004. In both periods, PIH was associated with a higher risk of stillbirth and neonatal death. We explored this in more detail in 2003-2004, and observed that the increased risk of PIH-related stillbirth was higher in women having their second or higher-order births (OR = 2.2 [95% confidence interval = 2.1-2.4]) compared with women having their first birth (1.5 [1.4-1.6]). Patterns were similar for neonatal death (1.3 [1.2-1.4] in first and 1.6 [1.5-1.8] in second or higher-order births). Among multiparas, the association between PIH and stillbirth was stronger in black women (2.9 [2.7-3.2]) than white women (2.0 [1.8-2.1]). Conclusions: A substantial burden of stillbirth and neonatal mortality is associated with PIH, especially among multiparous women, which may be due to more severe PIH, or to a higher burden of underlying disease. © 2009 by Lippincott Williams & Wilkins.


Oyelese Y.,University of Tennessee Health Science Center | Ananth C.V.,Gynecology and Reproductive science
Clinical Obstetrics and Gynecology | Year: 2010

Postpartum hemorrhage (PPH) is a leading cause of death and morbidity relating to pregnancy. Uterine atony is the leading cause of PPH, and trauma, including iatrogenic trauma, increases the risk for postpartum hemorrhage. Women with PPH in a pregnancy are at increased risk of PPH in a subsequent pregnancy. Awareness of these facts, and anticipation and prevention of uterine atony, as well as avoiding unnecessary cesareans, episiotomies, and other genital tract trauma have the potential to significantly reduce the mortality and morbidity from postpartum hemorrhage. The epidemiology of postpartum hemorrhage, including the incidence and temporal trends as well as the causes and risk factors associated with it are presented. © 2010, Lippincott Williams & Wilkins.


Pal L.,Gynecology and Reproductive science
Maturitas | Year: 2015

A fraction of cells residing in the uterine endometrium exhibit functional pluripotent potential, allowing them to be classified as adult stem cells. While the physiological relevance of this cell population is mostly conjectural at this juncture, uterine endometrial stem cells (UESC's) may underline pathogenesis of certain common gynecological disorders, such as endometriosis and adenomyosis. The ease of access and harvesting of UESC's and the diverse differentiation potential of this cell population has identified the uterine endometrium as a valuable source of autologous stem cells that can be harnessed through judicious application of principals of regenerative medicine. This mini review offers a glimpse into the journey, and an introduction to the spectrum of disorders that UESC's have the potential of impacting. © 2015 Elsevier Ireland Ltd.


Tidyman W.E.,University of California at San Francisco | Lee H.S.,University of California at San Francisco | Rauen K.A.,Gynecology and Reproductive science
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2011

Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are two of the more rare RASopathies caused by altered signal transduction of the Ras/mitogen-activated protein kinase (MAPK) pathway. All of the RASopathies exhibit some degree of hypotonia, but CS and CFC are more severe. To determine if individuals with CS and CFC have an underlying skeletal myopathy, we systematically evaluated skeletal muscle pathology in both conditions. We reviewed pathology reports from six individuals who had undergone a skeletal muscle biopsy, and we reviewed histology slides on two cases with CS and one case with CFC. All patients in the cohort had histopathologic findings, and two consistent abnormalities were identified. The first was the presence of abnormal muscle fiber size and variability, and the second was the presence of type 2 fiber predominance. Given the degree of hypotonia typically present in these patients, the overall architecture of the muscle was relatively normal, without showing indications of severe structural histopathology or metabolic abnormalities. Because the Ras/MAPK pathway is vital for skeletal myogenesis, we evaluated the effects of CS and CFC mutations on myogenesis using C2C12 myoblasts. All CS/CFC mutations inhibited myoblast differentiation as indicated by fewer myosin heavy chain expressing cells and a decrease in the number of myotubes as compared to controls. These findings indicate that CS and CFC may have a true myopathy related to an inherent dysregulation of skeletal myogenesis, which further expands our understanding of the consequences of germline Ras/MAPK mutations. © 2011 Wiley-Liss, Inc.


Wood M.A.,Gynecology and Reproductive science | Rajkovic A.,Gynecology and Reproductive science | Rajkovic A.,University of Pittsburgh
Seminars in Reproductive Medicine | Year: 2013

Ovarian reserve and its utilization, over a reproductive life span, are determined by genetic, epigenetic, and environmental factors. The establishment of the primordial follicle pool and the rate of primordial follicle activation have been under intense study to determine genetic factors that affect reproductive lifespan. Much has been learned from transgenic animal models about the developmental origins of the primordial follicle pool and mechanisms that lead to primordial follicle activation, folliculogenesis, and the maturation of a single oocyte with each menstrual cycle. Recent genome-wide association studies on the age of human menopause have identified approximately 20 loci, and shown the importance of factors involved in double-strand break repair and immunology. Studies to date from animal models and humans show that many genes determine ovarian aging, and that there is no single dominant allele yet responsible for depletion of the ovarian reserve. Personalized genomic approaches will need to take into account the high degree of genetic heterogeneity, family pedigree, and functional data of the genes critical at various stages of ovarian development to predict women's reproductive life span. Copyright © 2013 by Thieme Medical Publishers, Inc.


Wenner M.M.,The John B Pierce Laboratory | Taylor H.S.,Gynecology and Reproductive science | Stachenfeld N.S.,The John B Pierce Laboratory | Stachenfeld N.S.,Yale University
Journal of Physiology | Year: 2011

Women are more susceptible to orthostatic intolerance. Peripheral α-adrenergic responsiveness is important in orthostasis and is lower in women compared to men, and is modulated by female sex hormones. We tested the hypothesis that oestradiol attenuates peripheral cutaneous adrenergic responses in women with low orthostatic tolerance (LT), whereas progesterone enhances adrenergic responses in women with high orthostatic tolerance (HT). After completing a maximal lower body negative pressure test to determine level of orthostatic tolerance (cumulative stress index, CSI), women self administered a gonadotropin releasing hormone (GnRH) antagonist for 16 days to suppress endogenous sex hormone production. Oestradiol (E 2, 0.2 mg day -1, patch; days 4-16), and progesterone (P 4, 200 mg day -1, oral; days 12-16) were administered. Skin blood flow responses to graded intradermal microdialysis infusions of noradrenaline (NA) were measured during GnRH antagonist, E 2, and E 2+P 4, in eight HT (s.e.m.=22 ± 1 years, CSI -871 ± 86 mmHg min) and eight LT (21 ± 1 years, CSI -397 ± 65 mmHg min) women. In separate probes, NA was infused alone, and co-infused with the nitric oxide synthase inhibitor N G-monomethyl-l-arginine (l-NMMA, 10 mm), the non-selective cyclooxygenase inhibitor ketorolac tromethamine (Keto, 10 mm), and combined l-NMMA + Keto (10 mm each). Progesterone administration enhanced adrenergic responses in HT women (logEC 50 GnRH -4.02 ± 0.39, E 2+P 4-5.18 ± 0.31, P < 0.05); this response was reversed with Keto (E 2+P 4 logEC 50 NA+Keto -3.82 ± 0.35, P < 0.05). In contrast, no change in adrenergic responsiveness occurred in LT women during any hormone condition. These data indicate differential regulation of cutaneous adrenergic responses by progesterone via the cyclooxygenase pathway in women with high and low orthostatic tolerance. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.


Merhi Z.,Gynecology and Reproductive science | Irani M.,Maimonides Medical Center | Doswell A.D.,Gynecology and Reproductive science | Ambroggio J.,Gynecology and Reproductive science
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: The interaction of advanced glycation end-products (AGEs) with their cellular receptor (RAGE) is implicated in the pathogenesis of abnormal ovarian follicular growth. RAGE has a circulating secretory receptor form, soluble RAGE (sRAGE), which neutralizes the action of AGEs and might exert a protective role on the follicular environment. Objective: The objective of the study was to investigate whether serum or follicular fluid (FF) sRAGE levels are associated with markers of ovarian reserve. Design, Setting, and Participants: Serum anti-Mullerian hormone (AMH) and sRAGE protein levels were correlated in 31 reproductive-aged women. An additional 33womenwho underwent oocyte retrieval for in vitro fertilization were enrolled.AMHand its receptor (AMHR-II) mRNA levels were quantified in cumulus granulosa cells and FF sRAGE and AMH protein levels were measured. Main Outcome Measures: Granulosa cell AMH and AMHR-II gene expression, serum and FF AMH and sRAGE protein concentration, and number of oocytes retrieved were measured. Results: In the serum, sRAGE levels were negatively correlated with body mass index (BMI) (r = -0.5, P < .001) but not with age or serum AMH. The higher the FF sRAGE, the lower the number of international units of gonadotropinneededper cycle independent of age, BMI, or day 3FSHlevel (r=-0.4, P = .04). After adjusting for age, BMI, day 3 FSH, and the total dose of gonadotropins, FF sRAGE predicted the number of oocytes retrieved (R2 = 0.27, P = .045). FF sRAGE positively correlated with FF AMH levels (r = 0.5, P = .0085). RT-PCR results showed no correlation between the FF sRAGE and AMH or AMHR-II mRNA levels. Conclusion: These data support a relationship between FF sRAGE and measures of ovarian reserve. The pathological significance of the harmful inflammatory AGEs in follicular health clearly requires further investigation. Targeting AGEs might offer potential therapeutic options for the treatment of diminished ovarian response. Copyright © 2014 by the Endocrine Society.

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