FEMALE HORMONE REPLACEMENT

Mechanism for hormone heart protection, endothelial cells
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10 reasons for HRT
Mechanism for hormone heart protection, endothelial cells
Estrogen lowers breast cancer death rate
Breast Cancer Survival up with subsequent HRT
Estradiol with progesterone, natural HRT
Estradiol longevity and cardiovascular disease
Taxoxifen is not worth side effects
Estrogens provents hardening of the arteries thus cardiovascular disease
Setting the record straight with journal articles on HRT
HRT for Postmenopausal Women, and PhARMA Profits First
More Setting the Record Straight
HRT Studies, much fewer heart attacks, etc.
Breast-Firmer-HRT
Cholesterol profile improved by Estradiol
Cognitive functions improved
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healther skin with HRT
Bioidentical Hormone therapy advice
HRT benefits journals
Choice of progestagen component in HRT affects incidence of Breast cancer
HRT & Heart Benefits--etc.
22% muscle loss prevented with testosterone
Arthritis effective treatment HRT
Testosterone, Sex Drive, Feeling Better, etc--Mayo Clinic
Testosterone increases sexual drive
Testosterone improves sexual desire and sex
FDA Article on Menopause and HRT
Bioidentical Hormone therapy advice
Prempro settlement $330M
alcohol and higher estradiol and testosterone levels in postmenopausal women

As stated in the HRT position paper, which extols the benefits of natural HRT (estradiol and progesterone), namely, that these hormones (and for men Testosterone) send a message to body:   maintain a youthful state”.  The below articles document the youthful effect upon endothelial cells (prevents endothelial dysfunction) that line the blood vessels and thereby reduce the risk factor for cardiovascular disease and the associated strokes and heart attacks.  Decline in sex hormones has advantageous consequences for our hunter-gatherer clans from which are genetic foundations comes:  it culls the herd; viz., contributes to the removal of the burdensome less productive elderly.     Though the evidence is there, the opinion leaders giving the continuing education class and writing the textbooks  teach pharma’s position that hormone replacement is bad and.  Just scholar.google the topic or go to the AHA site and view the articles and references.  The body of experimental evidence confirms that natural hormones in sufficient dose prevent arteriosclerosis and thus cardiovascular disease.  Numerous epidemiological studies demonstrate this benefit.

Endothelial cells line the entire circulatory system, from the heart to the smallest capillaries. These cells have unique functions in vascular biology. These functions include fluid filtration, such as in the glomeruli of the kidney, blood vessel tone, hemostasis, neutrophil recruitment, and hormone trafficking.   Endothelium of the interior surfaces of the heart chambers is called endocardium.  FUNCTIONS:  Endothelial cells are involved in many aspects of vascular biology, including:

  • Barrier function - the endothelium acts as a semi-selective barrier between the vessel lumen and surrounding tissue, controlling the passage of materials and the transit of white blood cells into and out of the bloodstream. Excessive or prolonged increases in permeability of the endothelial monolayer, as in cases of chronic inflammation, may lead to tissue edema/swelling.
  • Blood clotting (thrombosis & fibrinolysis). The endothelium normally provides a non-thrombogenic surface because it contains, for example, heparan sulfate which acts as a cofactor for activating antithrombin, a protease that inactivates several factors in the coagulation cascade.
  • Inflammation
  • Formation of new blood vessels (angiogenesis)
  • Vasoconstriction and vasodilation, and hence the control of blood pressure
  • Repair of damaged or diseased organs via an injection of blood vessel cells[5]
  • Angiopoietin-2 works with VEGF to facilitate cell proliferation and migration of endothelial cells

Endothelial dysfunction, or the loss of proper endothelial function, is a hallmark for vascular diseases, and is often regarded as a key early event in the development of arteriosclerosis. Impaired endothelial function, causing hypertension and thrombosis, is often seen in patients with coronary artery disease, diabetes mellitus, hypertension, hypercholesterolemia, as well as in smokers. Endothelial dysfunction has also been shown to be predictive of future adverse cardiovascular events, and is also present in inflammatory disease such as rheumatoid arthritis and systemic lupus erythematosus.  Wiki

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http://circ.ahajournals.org/content/95/6/1505.short   Estradiol as a Survival Factor; 1997; 95: 1505-1514


Estrogen-Receptor–Mediated Inhibition of Human Endothelial Cell Apoptosis


Abstract:  Background A series of studies was performed to examine the ability of estradiol (E2) to protect endothelial cells from apoptosis.


Methods and Results Light and transmission electron microscopy demonstrated typical features of apoptosis in human umbilical vein endothelial cells (HUVEC) exposed to tumor necrosis factor-α (TNF-α). Northern and Western blot analyses revealed induction of message and protein for the interleukin-1β converting enzyme (ICE), which has been shown to mediate apoptosis induced by TNF-α. Immunofluorescent staining of HUVEC colocalized ICE expression to apoptotic HUVEC. Direct cell counting demonstrated a significant decrease in total endothelial cell number after 24 hours of TNF-α exposure and a dose-dependent reversal of the effect of TNF-α with E2 treatment. This protective effect was abrogated by an estrogen-receptor antagonist. Fluorescence-activated cell sorting analysis revealed 39.3% apoptosis after 24 hours of TNF-α exposure. Treatment with E2 resulted in a 50% decrease in apoptosis. Similarly, viability assays revealed 354% cell death after TNF-α exposure. Simultaneous treatment with E2 resulted in a dose-dependent reduction of cell death to a minimum of 182%. The protective effect of E2 was nullified by a specific estrogen-receptor antagonist.


Conclusions E2 treatment resulted in a dose-dependent, receptor-mediated inhibition of TNF-α–induced endothelial cell apoptosis. These studies indicate that E2 may also serve a maintenance function in preventing endothelial cell death after noxious stimuli and suggest that the ICE pathway may mediate cytokine-induced apoptosis in endothelial cells. Preservation of endothelial integrity represents another mechanism that may account for the atheroprotective effect of estrogen.


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I believe that the fall in testosterone level from the youth level explains the middle-age risk for men.  This decline has accelerated for men since 1910 in that there is nearly a 40% decline in testosterone when compared to that of a century ago—probably a result of dietary estrogen and testosterone mimics.   For article on population level decline:    http://jcem.endojournals.org/content/92/1/196.full


http://circ.ahajournals.org/content/103/10/1382.full?sid=ebc77905-be20-4f61-90c6-248cec066b77 Circulation. 2001; 103: 1382-1385


Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall


Abstract


Background—Recent studies have suggested that testosterone has a protective effect in the arterial vascular system. However, little is known about the molecular aspects of the mechanism(s) involved in these processes. The aim of the present study was to investigate the effect of testosterone on neointimal plaque development and on the expression of the vascular androgen receptor.


Methods and Results—Neointimal plaque formation was induced by endothelial denudation in the aortas of male New Zealand White rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses. Compared with the non–hormone-treated control group, a significant inhibition of neointimal plaque development (expressed as the intima/media ratio) was found at testosterone concentrations of 10 ng/mL (P=0.037) and 100 ng/mL (P=0.012; intima/media ratios: median of controls, 0.25; median of 10 ng/mL testosterone group, 0.15; median of 100 ng/mL testosterone group, 0.16). Associated with this inhibitory effect on plaque size was a 50% increase of the amount of androgen receptor mRNA in the arterial segments treated with testosterone.


ConclusionThe beneficial effects of testosterone on post injury plaque development underlines, at least in males, the important role of androgens in the vascular system. As our data suggest, the vascular androgen receptor is probably involved in these processes. Further studies are required to characterize the androgen receptor–dependent pathways in the vascular system.


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Numerous studies prove the protective effects of HRT—unfortunately they include all forms of estrogen and various progestins.  Given the rareness of MI in premenopausal women compared to men of similar age and the increase in events following menopause, this is strong evidence for the superiority of natural HRT.  Though I couldn’t find NHRT trials, because progesterone is not orally active and was not available as a pill until about 2005, when it was micronized in oil, the Danish study (below) using triphasic estradiol and norethisterone acetate is the closest I could find.  The frequency of major events, death, cancer, and heart failure, was reduced over 100% from 33 in the placebo group to 16 for those on HRT.  HRT was used for 11 years, and the women were tracked for 16 years.  They used the Danish national hospital registry to track outcomes “with an almost 100% completeness of recording and a high precision of diagnoses”.  Deaths due to cardiovascular causes occurred in 18 women in the control group and five in the treated group.” 



http://upload.wikimedia.org/wikipedia/commons/d/d0/Endotelijalna_%C4%87elija.jpg



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http://circ.ahajournals.org/content/126/16/1993.full?sid=f0c284a1-0bfb-4bfb-aa86-081f003c9c2c [FULL]  Circulation. 2012; 126: 1993-2004 Published online before print September 20, 2012

Rapid Estrogen Receptor Signaling Is Essential for the Protective Effects of Estrogen Against Vascular Injury

Abstract

Background—Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits arteriosclerosis. These effects are mediated by estrogen receptors (ERs), which, when bound to estrogen, can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a rapid nonnuclear signaling cascade. However, the biological significance of this rapid signaling pathway has been unclear.

Methods and Results—In the present study, we develop a novel transgenic mouse in which rapid signaling is blocked by overexpression of a peptide that prevents ERs from interacting with the scaffold protein striatin (the disrupting peptide mouse). Microarray analysis of ex vivo treated mouse aortas demonstrates that rapid ER signaling plays an important role in estrogen-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of estrogen to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the disrupting peptide mouse after carotid artery wire injury.

Conclusions—Taken together, these results support the concept that rapid, nonnuclear ER signaling contributes to the transcriptional regulatory functions of ER and is essential for many of the vaso-protective effects of estrogen [vaso vasorum]. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents. [Vaso vasorum are blood vessel that supply oxygen and nutrients to the cell in the artery wall.  Damaged vaso vasorum promote infection therein and arteriosclerosis. 

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http://circ.ahajournals.org/content/95/6/1505.short   Estradiol as a Survival Factor; 1997; 95: 1505-1514

Estrogen-Receptor–Mediated Inhibition of Human Endothelial Cell Apoptosis

Abstract:  Background A series of studies was performed to examine the ability of estradiol (E2) to protect endothelial cells from apoptosis.

Methods and Results Light and transmission electron microscopy demonstrated typical features of apoptosis in human umbilical vein endothelial cells (HUVEC) exposed to tumor necrosis factor-α (TNF-α). Northern and Western blot analyses revealed induction of message and protein for the interleukin-1β converting enzyme (ICE), which has been shown to mediate apoptosis induced by TNF-α. Immunofluorescent staining of HUVEC colocalized ICE expression to apoptotic HUVEC. Direct cell counting demonstrated a significant decrease in total endothelial cell number after 24 hours of TNF-α exposure and a dose-dependent reversal of the effect of TNF-α with E2 treatment. This protective effect was abrogated by an estrogen-receptor antagonist. Fluorescence-activated cell sorting analysis revealed 39.3% apoptosis after 24 hours of TNF-α exposure. Treatment with E2 resulted in a 50% decrease in apoptosis. Similarly, viability assays revealed 354% cell death after TNF-α exposure. Simultaneous treatment with E2 resulted in a dose-dependent reduction of cell death to a minimum of 182%. The protective effect of E2 was nullified by a specific estrogen-receptor antagonist.

Conclusions E2 treatment resulted in a dose-dependent, receptor-mediated inhibition of TNF-α–induced endothelial cell apoptosis. These studies indicate that E2 may also serve a maintenance function in preventing endothelial cell death after noxious stimuli and suggest that the ICE pathway may mediate cytokine-induced apoptosis in endothelial cells. Preservation of endothelial integrity represents another mechanism that may account for the atheroprotective effect of estrogen.

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

I believe that the fall in testosterone level from the youth level explains the middle-age risk for men.  This decline has accelerated for men since 1910 in that there is nearly a 40% decline in testosterone when compared to that of a century ago—probably a result of dietary estrogen and testosterone mimics.   For article on population level decline:    http://jcem.endojournals.org/content/92/1/196.full

http://circ.ahajournals.org/content/103/10/1382.full?sid=ebc77905-be20-4f61-90c6-248cec066b77 Circulation. 2001; 103: 1382-1385

Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall

Abstract

Background—Recent studies have suggested that testosterone has a protective effect in the arterial vascular system. However, little is known about the molecular aspects of the mechanism(s) involved in these processes. The aim of the present study was to investigate the effect of testosterone on neointimal plaque development and on the expression of the vascular androgen receptor.

Methods and Results—Neointimal plaque formation was induced by endothelial denudation in the aortas of male New Zealand White rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses. Compared with the non–hormone-treated control group, a significant inhibition of neointimal plaque development (expressed as the intima/media ratio) was found at testosterone concentrations of 10 ng/mL (P=0.037) and 100 ng/mL (P=0.012; intima/media ratios: median of controls, 0.25; median of 10 ng/mL testosterone group, 0.15; median of 100 ng/mL testosterone group, 0.16). Associated with this inhibitory effect on plaque size was a 50% increase of the amount of androgen receptor mRNA in the arterial segments treated with testosterone.

ConclusionThe beneficial effects of testosterone on post injury plaque development underlines, at least in males, the important role of androgens in the vascular system. As our data suggest, the vascular androgen receptor is probably involved in these processes. Further studies are required to characterize the androgen receptor–dependent pathways in the vascular system.

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

Numerous studies prove the protective effects of HRT—unfortunately they include all forms of estrogen and various progestins.  Given the rareness of MI in premenopausal women compared to men of similar age and the increase in events following menopause, this is strong evidence for the superiority of natural HRT.  Though I couldn’t find NHRT trials, because progesterone is not orally active and was not available as a pill until about 2005, when it was micronized in oil, the Danish study (below) using triphasic estradiol and norethisterone acetate is the closest I could find.  The frequency of major events, death, cancer, and heart failure, was reduced over 100% from 33 in the placebo group to 16 for those on HRT.  HRT was used for 11 years, and the women were tracked for 16 years.  They used the Danish national hospital registry to track outcomes “with an almost 100% completeness of recording and a high precision of diagnoses”.  Deaths due to cardiovascular causes occurred in 18 women in the control group and five in the treated group.” 

Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

Cite this as: BMJ 2012;345:e6409    http://www.bmj.com/content/345/bmj.e6409?etoc

  Participants 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone.

Interventions In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years.

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Extract by JK from the highly regarded Harvard Nurse’s Health Study.  This population study includes all forms of HRT including Prempro, the worse.  Over 70,000 nurses participated in the study. 

http://test.europepmc.org/abstract/MED/1870648 http://test.europepmc.org/wicket/resource/uk.bl.ukpmc.web.pages.main.Home/images/small_clipboard_off-ver-0CF126D6BE0C2618F52BA585360BFB49.gif NEJM 1991, 325(11):756-762

Postmenopausal estrogen therapy & cardiovascular disease. Ten-year follow-up from the nurses' health study.

RESULTS: After adjustment for age and other risk factors, the overall relative risk of major coronary disease in women currently taking estrogen was 0.56 (95 percent confidence interval, 0.40 to 0.80); the risk was significantly reduced among women with either natural or surgical menopause. We observed no effect of the duration of estrogen use independent of age.

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1997; 96: 2468-2482   This article besides the major CHD benefit of HRT, showed that it was well documented the adverse effects of MPA used in Prempro for the HRT in the landmark NIH’s Women’s Health Initiative (WHI). 

Cardiovascular Disease in Women

A Statement for Healthcare Professionals From the American Heart Association

http://circ.ahajournals.org/content/96/7/2468.full

Based on meta-analyses of studies, most from the United States,184 185 postmenopausal estrogen is associated with a 35% to 50% reduced risk of CHD. On the basis of a calculation of overall risks and benefits, a healthy woman at no particular increased risk for heart disease, cancer, or osteoporosis would gain on average 1 additional year of life.185   As reviewed elsewhere,188 189 there are multiple mechanisms whereby estrogen might protect against CHD, including favorable changes in lipids, lipoproteins, fibrinogen and PAI-1, vasomotor effects, and antioxidant effects.  In a recent study,192 232 women who had used estrogen since menopause for an average duration of 17 years had nearly 50% lower mortality from all causes than age-matched nonusers (95% CI=0.38-0.76); reduced mortality was largely due to less fatal CVD.  A report from the Nurses’ Health Study 187 showed a reduced risk of nearly every disease except breast cancer. A recent Markov analysis193 postulated a 3-year increase in life expectancy associated with use of postmenopausal estrogen….  These studies had relatively few events, however, and several new lines of evidence suggest that medroxyprogesterone acetate may mask or at least partially reverse estrogen-induced benefits.    Other studies show that medroxyprogesterone acetate can have a particularly deleterious effect on estrogen-induced improvements in vascular reactivity and arteriosclerosis.  For example, recent studies in nonhuman primates showed that conjugated equine estrogen alone—but not estrogen combined with medroxyprogesterone acetate—improved vascular reactivity of coronary arteries198 and prevented the progression of coronary artery arteriosclerosis.199  

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