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Alexandra D Ogorodnikova,
Unab I Khan,
Aileen P McGinn,
Irfan Zeb,
Matthew J Budoff,
S M Harman,
Virginia M Miller,
Eliot A Brinton,
Joann E Manson,
Howard N Hodis,
George R Merriam,
Marcelle I Cedars,
Hugh S Taylor, Frederick Naftolin,
Rogerio A Lobo,
Nanette Santoro,
Rachel P Wildman
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ABSTRACT: OBJECTIVE: It is unclear why despite a comparable cardiometabolic risk profile, "metabolically benign" overweight/obese individuals show an elevated risk of cardiovascular disease compared to normal weight individuals. DESIGN AND METHODS: In cross-sectional analyses, we compared levels of ectopic fat (epicardial, pericardial, and hepatic fat) and adipokines (leptin, soluble leptin receptor, and high molecular weight [HMW] adiponectin) among metabolically benign (MBO) and at-risk overweight/obese (ARO), and metabolically benign normal weight (MBNW) women, screened for the Kronos Early Estrogen Prevention Study. We defined "metabolically benign" with ≤ 1, and "at-risk" with ≥2 components of the metabolic syndrome. RESULTS: Compared to MBO women, ARO women had significantly elevated odds of being in the top tertile of epicardial fat (OR: 1.76, 95% CI: 1.04-2.99), hepatic fat (OR: 1.90, 95% CI:1.12-3.24) and leptin (OR: 2.15, 95% CI: 1.23-3.76), and the bottom tertile of HMW-adiponectin (OR: 2.90, 95% CI: 1.62-5.19). Compared to MBNW women, MBO women had significantly higher odds of being in the top tertile of epicardial fat (OR: 5.17, 95% CI: 3.22-8.29), pericardial fat (OR: 9.27, 95% CI: 5.52-15.56) and hepatic fat (OR: 2.72, 95% CI: 1.77-4.19) and the bottom tertile of HMW adiponectin levels (OR: 2.51, 95% CI: 1.60-3.94). CONCLUSIONS: Levels of ectopic fat and the adverse adipokine profile increase on a continuum of BMI, suggesting that the metabolically benign phenotype may be a transient state.
Obesity 11/2012; · 4.28 Impact Factor
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Virginia M Miller,
Tanya M Petterson,
Elysia N Jeavons,
Abhinita S Lnu,
David N Rider,
John A Heit,
Julie M Cunningham,
Gordon Spencer Huggins,
Howard N Hodis,
Matthew J Budoff,
Nanette Santoro,
Paul N Hopkins,
Rogerio A Lobo,
Joann E Manson, Frederick Naftolin,
Hugh S Taylor,
S Mitchell Harman,
Mariza de Andrade
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ABSTRACT: Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but pose a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic or innate immunity pathways. Using linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, β = 0.037, p-value = 2.36x10(-06)), and one on chromosome 5 for IL5 gene (rs739318, β = 0.051, p-value = 5.02x10(-05)) associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, β = -0.043, p-value = 3.59x10(-05); rs2291299, β = -0.032, p-value = 5.59x10(-05)) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, adjusting for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, p-value = 1.10x10(-04); and rs17751769, SERPINA1, chromosome 14, OR = 1.96, p-value = 2.42x10(-04)) associated positively with a CAC score of >0 AU; one SNP (rs630014, ABO, OR = 0.51, p-value = 2.51x10(-04)) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.
Physiological Genomics 11/2012; · 2.73 Impact Factor
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ABSTRACT: In 2005, the National Institute of Dental and Craniofacial Research / National Institute of Health (NIDCR/NIH) funded the largest initiative to date to affect change in the delivery of oral care. This commentary provides the background for the first study related to periodontics in a Practice Based Research Network (PBRN). It was conducted in the PEARL (Practitioners Engaged in Applied Research & Learning) Network. The PEARL Network is headquartered at New York University College of Dentistry. The basic tenet of the PBRN initiative is to engage clinicians to participate in clinical studies, where they will be more likely to accept the clinical results and to incorporate the findings into their practice. This process may reduce the translational gap that exists between new findings and the time it takes for those findings to be incorporated into clinical practice. The cornerstone of the PBRN studies is to conduct comparative effectiveness research studies to disseminate findings to the profession and improve care. This is particularly important as the majority of dentists practice independently. Having practitioners generate clinical data allows them to contribute in the process of knowledge development and incorporate the results in their practice to assist in closing the translational gap. With the advent of electronic health systems on the horizon dentistry may be brought into the mainstream health care paradigm and the PBRN concept can serve as the skeletal framework for advancing the profession provided there is consensus on the terminology used.
Journal of Periodontology 06/2012; · 2.60 Impact Factor
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ABSTRACT: We have shown that ezrin expression correlates with ovarian epithelial cancer (OVCA) cell proliferation and metastatic behavior. In this study, we evaluated ezrin expression in transformed ovarian superficial epithelial cells (OSE) in ovarian clefts and in culture.
Immunohistochemistry and Western blotting for immunoreactive ezrin (ir-ezrin) in normal ovarian tissue, cultured OSE, and ovarian epithelial cancer cells.
While ir-ezrin was not demonstrable in normal cuboidal surface cells or interior ovarian organelles, cells lining the ovarian clefts strongly expressed ir-ezrin. Long-term culture of OSE increased ezrin expression and cytological abnormalities. Administration of estradiol and insulin at levels reported in inclusions dramatically induced OSE ir-ezrin expression to OVCA levels and membrane specializations; ruffling, pseudopodia and filopodia. Moreover epidermal growth factor (EGF) drastically increased ezrin translocation in OSE cells in a time-dependent manner.
Ezrin expression by OSE increases during transformation. Ezrin expression is responsive to estradiol and growth factors previously shown to be present in ovarian inclusions. These findings suggest that the microenvironment in ovarian inclusions and clefts contributes to the development of OVCA. Our findings elaborate on the mechanism of the ovarian origin of OVCA.
Reproductive sciences (Thousand Oaks, Calif.) 04/2012; 19(8):797-805. · 2.31 Impact Factor
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Gynecological Endocrinology 03/2012; 28 Suppl 1:1. · 1.58 Impact Factor
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ABSTRACT: To examine total ezrin expression (ezrin and phospho-ezrin) through the normal endometrial cycle and to correlate ezrin activation and localization with cytologic changes.
Experimental laboratory study.
University medical centers.
Reproductive-age women.
A total of 36 samples of normal early, mid-, and late proliferative- and secretory-phase endometrium were studied for immunoreactive total ezrin (ir-T-ezrin) and phospho-ezrin (ir-p-ezrin) expression by histology, immunohistochemistry, and Western blotting.
Total ezrin and phospho-ezrin expressions through the normal endometrial cycle.
Throughout the cycle ir-T-ezrin is present in the epithelium. The intensity and localization of both ir-ezrin and ir-p-ezrin vary greatly throughout the cycle. The main findings include the following: lateral localization of ir-ezrin/ir-p-ezrin in association with membrane specializations; dense staining around secretory vacuoles (secretory phase); dense staining of the apical surfaces, including microvilli and pinopodes of epithelial cells, especially during the mid- to late secretory phases; and the presence of ezrin in the glandular secretions. Immunoreactive total ezrin and ir-p-ezrin were not expressed by stromal fibroblasts.
Ezrin is a prominent protein in the cycling endometrium. The most striking findings were the gravitation of ir-ezrin/ir-p-ezrin to the periphery of secretory vacuoles, localization on apical surfaces of the luminal epithelium, dense ezrin staining in secretory-phase epithelial cell plumes, and the presence of ir-ezrin/ir-p-ezrin in secretory-phase luminal secretions. These findings may have functional implications, especially for implantation biology.
Fertility and sterility 01/2012; 97(1):192-9.e2. · 3.97 Impact Factor
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ABSTRACT: Adhesion of monocytes to vascular endothelium is necessary for atheroma formation. This adhesion requires binding of endothelial neural cell adhesion molecule (NCAM) to monocyte NCAM. NCAM:NCAM binding is blocked by sialylation of NCAM (polysialylated NCAM; PSA-NCAM). Since estradiol (E2) and dihydrotestosterone (DHT) induced PSA-NCAM and decreased monocyte adhesion, in consideration of possible clinical applications we tested whether their prohormone dehydroepiandrosterone (DHEA) has similar effects.
(1) DHEA was administered to cultured human coronary artery endothelial cells (HCAECs) from men and women. Monocyte binding was assessed using fluorescence-labeled monocytes. (2) HCEACs were incubated with E2, DHT, DHEA alone, or with trilostane, fulvestrant or flutamide. Expression of PSA-NCAM was assessed by immunohistochemistry and Western blotting.
Dehydroepiandrosterone inhibited monocyte adhesion to HCAECs by ≥50% (P < .01). Fulvestrant or flutamide blockade of DHEA's inhibition of monocyte binding appeared to be gender dependent. The DHEA-induced expression of PSA-NCAM was completely blocked by trilostane.
In these preliminary in vitro studies, DHEA increased PSA-NCAM expression and inhibited monocyte binding in an estrogen- and androgen receptor-dependent manner. Dehydroepiandrosteroneappears to act via its end metabolites, E2 and DHT. Dehydroepiandrosterone could furnish clinical prevention against atherogenesis and arteriosclerosis.
Reproductive sciences (Thousand Oaks, Calif.) 01/2012; 19(1):86-91. · 2.31 Impact Factor
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Gary Huang,
Dan Wang,
Irfan Zeb,
Matthew J Budoff,
S Mitchell Harman,
Virginia Miller,
Eliot A Brinton,
Samar R El Khoudary,
JoAnn E Manson,
MaryFran R Sowers,
Howard N Hodis,
George R Merriam,
Marcelle I Cedars,
Hugh S Taylor, Frederick Naftolin,
Rogerio A Lobo,
Nanette Santoro,
Rachel P Wildman
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ABSTRACT: To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women.
Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n=650).
Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r=0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides=-0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4-1.6], 1.5 [0.8-2.9], and 1.8 [1.0-3.4]; p for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat.
While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.
Atherosclerosis 12/2011; 221(1):198-205. · 3.79 Impact Factor
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ABSTRACT: Practice-based research networks (PBRNs) provide a novel venue in which providers can increase their knowledge base and improve delivery of care through participation in clinical studies. This article describes some aspects of our experience with a National Institute of Dental and Craniofacial Research-supported PBRN and discusses the role it can play in dental education. PBRNs create a structured pathway for providers to advance their professional development by participating in the process of collecting data through clinical research. This process allows practitioners to contribute to the goals of evidence-based dentistry by helping to provide a foundation of evidence on which to base clinical decisions as opposed to relying on anecdotal evidence. PBRNs strengthen the professional knowledge base by applying the principles of good clinical practice, creating a resource for future dental faculty, training practitioners on best practices, and increasing the responsibility, accountability, and scope of care. PBRNs can be the future pivotal instruments of change in dental education, the use of electronic health record systems, diagnostic codes, and the role of comparative effectiveness research, which can create an unprecedented opportunity for the dental profession to advance and be integrated into the health care system.
Journal of dental education 08/2011; 75(8):1053-60. · 0.91 Impact Factor
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ABSTRACT: Contemporary women have long life expectancy (81 y, United States), especially relative to the age at menopause (51 y, United States). Menopause is a consequence of reproductive aging and follicular depletion (ovarian failure), yielding very low circulating estrogen serum concentrations and biologically disadvantageous metabolic alterations. Stated in terms of antagonistic pleiotropy, the ongoing hypoestrogenic endocrine environment, beneficial during lactation, results in acceleration of several age-related illnesses after menopause (ie, late postmenopausal osteoporosis, cardiovascular disease, and cognitive decline). Specifically, the similar hypoestrogenic hormonal milieu present during postpartum lactation provides biologic advantages (fitness) to both mother and newborn. These precepts of evolutionary medicine encourage a reassessment of hormone therapy, and on the basis of data presented the authors propose additional opportunities for disease prevention and morbidity reduction in postmenopausal women.
Menopause (New York, N.Y.) 03/2011; 18(3):336-42. · 3.08 Impact Factor
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S Mitchell Harman,
Eric Vittinghoff,
Eliot A Brinton,
Matthew J Budoff,
Marcelle I Cedars,
Rogerio A Lobo,
George R Merriam,
Virginia M Miller, Frederick Naftolin,
Lubna Pal,
Nanette Santoro,
Hugh S Taylor,
Dennis M Black
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ABSTRACT: Largely on the basis of the first publication of findings of net harm with menopausal hormone treatment in the Women's Health Initiative (WHI) hormone trials, current Food and Drug Administration recommendations limit menopausal hormone treatment to the "…shortest duration consistent with treatment goals…," with goals generally taken to mean relief of menopausal symptoms and maximal duration as approximately 5 years. The WHI finding of net harm was due largely to the absence of beneficial effects on coronary heart disease incidence rates. Published analyses of WHI data by age or time since menopause find that excess coronary heart disease risk with menopausal hormone treatment is confined to more remotely menopausal or older women, with younger women showing nonsignificant trends toward benefit (the "timing hypothesis"). Moreover, a recently published reexamination of data from the WHI Estrogen plus Progestin trial suggests that reduced coronary heart disease risk may appear only after 5 to 6 years of treatment. Consistent with this finding, risk ratios for coronary heart disease were calculated as 1.08 (95% confidence interval, 0.86-1.36) in years 1 to 6 and as 0.46 (confidence interval, 0.28-0.78) in years 7 to 8+ in the WHI Estrogen Alone trial. Previous studies also support the beneficial effects of menopausal hormone treatment after prolonged exposure. Thus, current analyses do not support a generalized recommendation for short duration of menopausal hormone treatment. Rather, they suggest that current Food and Drug Administration practice guidelines should be reconsidered to allow individualized care based on risk:benefit considerations. New research is urgently needed evaluating influences of timing, duration, dose, route of administration, and agents on menopausal hormone treatment-related risks and benefits to better understand how to optimize recommendations for individual patients.
The American journal of medicine 03/2011; 124(3):199-205. · 4.47 Impact Factor
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Annals of internal medicine 02/2011; 154(3):211-2; author reply 212-3. · 16.73 Impact Factor
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ABSTRACT: The mechanism of atherogenesis includes leukocyte adhesion to endothelial cells followed by migration into the subendothelial space. The polysialylated neural cell adhesion molecules (PSA-nCAMs) are a group of hydrophilic neural cell adhesion molecule (NCAM) isoforms that inhibit NCAM: NCAM association, thereby blocking cell: cell adhesion. During previous studies, we demonstrated that sialylation of specific NCAMs are upregulated at proestrus in the rat and that PSA-nCAM is expressed by the rat vascular endothelium.
In this study, we sought the presence of PSA-nCAM in human vessels and regulation of its expression in estradiol-treated human umbilical vascular endothelial cells (HUVEC). Immunoreactive PSA-nCAM (ir-PSA-nCAM) was shown in blood and lymph vessels of adult rats and human brain, skin, liver, lung, cervix, endometrium, and ovary. Staining for ir-PSA-nCAM was present on the glycocalyceal surface of estradiol-treated HUVEC, but not in the presence of the estrogen receptor (ER)-blocker fulvestrant. Western blotting confirmed these findings.
PSA-nCAM is widely present in the glycocalyx of human and rat vascular endothelium. It also is expressed by HUVEC, in which it is induced by estradiol. The estrogen-regulated presence of vascular PSA-nCAM could diminish NCAM-dependent interactions between vessels and circulating leukocytes, thereby impeding vascular inflammation and atherogenesis, and, contributing to estrogen-induced cardioprotection. This hypothesized action is presently under study.
Reproductive sciences (Thousand Oaks, Calif.) 12/2010; 17(12):1090-8. · 2.31 Impact Factor
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ABSTRACT: The purpose of this study was to assess the effect of DT56a (Femarelle), a selective estrogen receptor modulator, on platelet function in normal and thrombophilic women being treated for severe menopausal symptoms.
The Platelet Function Analyzer-100 (PFA-100) was used to asses platelet reactivity at baseline and after 8 weeks of treatment with Femarelle (644 mg/d in divided doses) in 25 symptomatic postmenopausal women with normal clotting times and seven symptomatic women with shortened clotting times (<61 s). The PFA-100 measure of closure time is considered equal to clotting time in assessing clotting function and platelet adhesion, aggregation, and blood coagulation factors. Closure times were measured after 3 and 8 weeks in all participants and at 1 year in the women with shortened clotting times. The nonparametric Wilcoxon signed rank test was used to assess the changes between baseline and each of the three subsequent measurements.
Pretreatment study of all seven women with shortened closure times confirmed abnormalities associated with thrombophilia: four women were heterozygous for the factor V Leiden gene mutation, one was heterozygous for the prothrombin gene mutation, one was found to have protein S deficiency, and one had increased anticardiolipin antibodies. All participants reported improved symptoms during the treatment period. No significant change in closure times was found in the normally clotting participants after 3 or 8 weeks of Femarelle therapy (P > 0.26). No significant change in closure time was seen in the seven thrombophilic women after 3 or 8 weeks or 1 year of Femarelle treatment (P > 0.26). The regression curve for measures over time was not significant (P = 0.26).
Femarelle, whose active ingredient is DT56a, did not adversely affect platelet reactivity as measured by PFA closure times in symptomatic thrombophilic postmenopausal women or normal controls. Femarelle, a novel selective estrogen receptor modulator that inhibits menopausal symptoms without thrombogenicity, may offer a new clinical choice for therapy of symptomatic postmenopausal women.
Menopause (New York, N.Y.) 10/2010; 18(3):285-8. · 3.08 Impact Factor
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Annals of internal medicine 07/2010; 153(1):60-1; author reply 61-2. · 16.73 Impact Factor
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Gynecological Endocrinology 02/2010; 26(6):391-2. · 1.58 Impact Factor
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ABSTRACT: To correlate angiotensin II (AngII) receptor expression by granulosa-lutein (GL) cells from gonadotropin-stimulated follicles with infertility diagnosis and IVF parameters.
The mRNA of angiotensin receptors type 1 (AT1) and type 2 (AT2) was studied in aspirated GL cells.
University laboratory and private IVF center.
Seventy-three IVF patients.
Reverse-transcription polymerase chain reaction analysis for relative expression of AT1 and AT2 receptor mRNA in women with no ovarian factor (NOF), poor ovarian reserve (PR), endometriosis (ENDO), and polycystic ovary syndrome (PCOS).
Expression of AT1 and AT2 receptor mRNA.
There was a constant approximately 7:1 ratio between AT1 and AT2 receptors and a negative correlation between the AT1/AT2 ratio and patient age. There were statistically significant differences in AngII receptors in individual conditions: NOF showed a correlation between AT1 and AT2 receptors and a negative correlation between AT1 receptor expression, embryo fragmentation and number of metaphase II (MII) oocytes; PR showed a negative correlation between AT2 receptor expression and number of MII oocytes; PCOS AT1 receptor expression correlated negatively with the units of FSH administered and with patients' age; ENDO showed no significant correlations.
Mural GL cells express AT1 receptor much more than AT2 receptor. AngII receptor expression varies with age and infertility diagnosis. Low expression of AngII receptors was associated with high-dose stimulation in women with PR. Embryo fragmentation in NOF is associated with decreased AT1 receptor expression, supporting a role for AngII in GL cell apoptosis.
Fertility and sterility 07/2009; 93(5):1601-8. · 3.97 Impact Factor
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ABSTRACT: Estrogen-induced synaptic plasticity (EISP) in the periventricular area (PVA) of the hypothalamus is necessary for the preovulatory gonadotropin surge. Because in situ enzymatic desialization of hypothalamic polysialylated (PSA) neural cell adhesion molecule (NCAM) blocked EISP, we examined the presence and amount of NCAM isotopes, PSA-NCAM, and sialylation enzymes in microdissected mouse hypothalamus tissues from proestrous afternoon [peak of estrogens and nadir of arcuate nucleus (AN) synapses] and metestrous morning (nadir of estrogens and highest AN synapses). Immunohistochemistry confirmed immunoreactive (ir) PSA-NCAM staining in the perineural spaces of the PVA. The extent of staining was cycle dependent, with more dense and complete profiles of individual neurons limned by the ir-PSA-NCAM staining on proestrus and less on metestrus. Western blots showed that high levels of ir-PSA-NCAM on proestrus are accompanied by diminished ir-NCAM-140 and -180 but not ir-NCAM-120 and the reverse on metestrus (P < 0.05). To evaluate the increase of sialylated NCAM at the expense of desialylated protein, expression of the responsible polysialyltransferase enzymes polysialyltransferase (ST8Sia IV) and sialyltransferase (ST8Sia II) mRNA levels were measured using RT-PCR. Both polysialyltransferase and sialyltransferase mRNA are more abundant on proestrus than metestrus (P < 0.05), indicating that these enzymes are regulated by estrogens. These results support estrogen-regulated formation and extrusion of hydrophilic PSA-NCAM into perineural spaces in the PVA as part of the mechanism of EISP.
Endocrinology 03/2009; 150(6):2783-90. · 4.46 Impact Factor
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ABSTRACT: Design faults resulted in the inability of the Women's Health Initiative (WHI) randomized clinical trial to test the level of cardioprotection conferred by timely hormone treatment of women seeking help for menopausal complaints. Adopting a design constructed around the avoidance of symptomatic subjects and recruitment of older subjects who were more likely to manifest cardiovascular events during the life of the WHI resulted in recruitment of older, sicker subjects than are normally treated for complaints around the time of menopause. The lack of cardioprotection in subjects that began treatment a decade or more after menopause diluted cardioprotection in subjects starting treatment close to the menopausal transition. As a result, despite having the largest number of subjects ever, there were not enough women in the WHI who were comparable to those in the observational trials that showed cardioprotection. This led the WHI to report that there was no cardioprotection in the trial, a position that has been qualified after further analysis. Misapprehension of the initial WHI conclusions by the media, professionals, and regulatory agencies led to a major shift away from menopausal hormone treatment. This remains problematic since the evidence continues to favor cardioprotection and other benefits that are denied under present regulations and guidelines. Regulatory agencies and professional organizations need to better understand the faws in the WHI design and results in order to properly consider its results and the sustainability of their earlier conclusions and recommendations. Additionally, new trials are needed to test the validity of menopausal hormone-related cardioprotection.
Bulletin of the NYU hospital for joint diseases 02/2009; 67(2):226-9.
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ABSTRACT: To test whether angiotensin II (AngII) could modulate apoptosis of human granulosa-lutein (GL) cells from gonadotropin-stimulated follicles.
In vitro assays on mural and cumulus granulosa cells.
University laboratory and private IVF practice.
One hundred six consecutive women undergoing 113 IVF cycles.
Purified human GL mural or cumulus cells were cultured in serum-free media in the presence or absence of AngII with or without the AngII receptor blockers saralasin and CGP42112A.
Detection of apoptosis using a fluorescent in situ marker for activated caspases.
Mural cells had approximately eightfold the amount of apoptosis compared with cumulus cells (average 0.23 vs. <0.03, respectively). With mural cells, AngII increased GL cell apoptosis versus untreated control samples (AngII 10(-)11 mol/L +6.5%; AngII 10(-9) mol/L +13.3%, and AngII 10(-7) mol/L +11.3%), an effect which was blocked by concurrent incubation with AngII receptor blockers. The AngII receptor blockers produced a significant decrease of apoptosis compared with control cultures (saralasin: 19.4%; CGP42112A: 28.9%). Neither AngII nor blockers had effect on cumulus cells.
Preovulatory concentrations of AngII, most likely via AT2 receptors, increase apoptosis of cultured mural GL cells but have no effect on cumulus cells. Granulosa cells appear to be differentially regulated by AngII.
Fertility and sterility 08/2008; 91(5 Suppl):1984-9. · 3.97 Impact Factor
