FEMALE HORMONE REPLACEMENT

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Epidemiological studies have shown a 50% reduction in coronary heart disease (CHD) after estrogen replacement therapy (ERT) in postmenopausal women (1-2). This protective effect of estrogen is presumably due to its ability to favorably alter low/high density lipoprotein (LDL/HDL) ratios and decrease vascular reactivity and oxidative stress (3)….  Brazilian Journal of Medical and Biological Research, Braz J Med Biol Res vol.35 no.3 RibeirŃo Preto Mar. 2002 at http://www.scielo.br/scielo.php?pid=S0100-879X2002000300001&script=sci_arttext&tlng=en

Epidemiological Studies showing MI reduction

1. Barrett-Connor E & Grady D (1998). Hormone replacement therapy, heart disease and other considerations. Annual Review of Public Health, 19: 35-72.    

2. Stampfer MJ & Colditz GA (1991). Estrogen replacement therapy and coronary heart disease: a quantitative assessment of epidemiological evidence. Preventive Medicine, 20: 47-63.     

Large numbers of hormone replacement therapies (HRTs) are available for the treatment of menopausal symptoms. It is still unclear whether some are more deleterious than others regarding breast cancer risk. The goal of this study was to assess and compare the association between different HRTs and breast cancer risk, using data from the French E3N cohort study. Invasive breast cancer cases were identified through biennial self-administered questionnaires completed from 1990 to 2002. During follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women. Compared with HRT never-use, use of estrogen alone was associated with a significant 1.29-fold increased risk (95% confidence interval 1.02–1.65). The association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83–1.22) for estrogen–progesterone, 1.16 (0.94–1.43) for estrogen–dydrogesterone, and 1.69 (1.50–1.91) for estrogen combined with other progestagens. This latter category involves progestins with different physiologic activities (androgenic, nonandrogenic, antiandrogenic), but their associations with breast cancer risk did not differ significantly from one another. This study found no evidence of an association with risk according to the route of estrogen administration (oral or transdermal/percutaneous). These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone

 

*  estrogen-progesterone group was rated at 1.00, those who never used estrogen at 1.29, thus a 29% reduction
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Estrogen's protective mechanism

An excellent review paper of HRT with information on methods of action.  There is a vast difference between Prempro, the worst of HRTs, and the natural alternatives of estradiol and progesterone.  Prempro was used by the 3 purportedly definitive studies mentioned in the Abstract

Brazilian Journal of Medical and Biological Research

On-line version ISSN 1414-431X

Braz J Med Biol Res vol.35 no.3 RibeirŃo Preto Mar. 2002

http://dx.doi.org/10.1590/S0100-879X2002000300001  

Braz J Med Biol Res, March 2002, Volume 35(3) 271-276 (Mini-Review)

Estrogen replacement therapy and cardio-protection: mechanisms and controversies

M.T.R. Subbiah

Division of Endocrinology, Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA

Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/down.gif Abstract 
Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/down.gif Text 
Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/down.gif References 
Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/down.gif Acknowledgments 
Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/down.gif Correspondence and Footnotes

Abstract Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/back.gif

Epidemiological and case-controlled studies suggest that estrogen replacement therapy might be beneficial in terms of primary prevention of coronary heart disease (CHD). This beneficial effect of estrogens was initially considered to be due to the reduction of low density lipoproteins (LDL) and to increases in high density lipoproteins (HDL). Recent studies have shown that estrogens protect against oxidative stress and decrease LDL oxidation. Estrogens have direct effects on the arterial tissue and modulate vascular reactivity through nitric oxide and prostaglandin synthesis. While many of the effects of estrogen on vascular tissue are believed to be mediated by estrogen receptors a and ▀, there is evidence for `immediate non-genomic' effects. The role of HDL in interacting with 17▀-estradiol including its esterification and transfer of esterified estrogens to LDL is beginning to be elucidated. Despite the suggested positive effects of estrogens, two recent placebo-controlled clinical trials in women with CHD did not detect any beneficial effects on overall coronary events with estrogen therapy. In fact, there was an increase in CHD events in some women. Mutations in thrombogenic genes (factor V Leiden, prothrombin mutation, etc.) in a subset of women may play a role in this unexpected finding. Thus, the cardioprotective effect of estrogens appears to be more complicated than originally thought and requires more research.

Key words: Estrogen therapy, Postmenopausal women, Cardiovascular disease, Plasma lipoproteins, Lipoprotein oxidation, Estrogen receptors, Thrombosis, Nitric oxide synthesis


Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/back.gif

Introduction

Epidemiological studies have shown a 50% reduction in coronary heart disease (CHD) after estrogen replacement therapy (ERT) in postmenopausal women (1-2). This protective effect of estrogen is presumably due to its ability to favorably alter low/high density lipoprotein (LDL/HDL) ratios and decrease vascular reactivity and oxidative stress (3). Three major placebo-controlled trials designed to study whether ERT reduces CHD have questioned this protective effect of estrogen. The Heart and Estrogen/Progestin Replacement Study (HERS) was the first placebo-controlled trial. HERS noted that ERT not only failed to reduce the overall rate of coronary events, but actually increased CHD in the first year with a 89% increase in thromboembolic events [used Prempro, the worst of HRTs].  (4). In the Estrogen and Atherosclerosis (ERA) Trial (5) there was no decrease in coronary artery disease progression with ERT in postmenopausal women with at least one coronary artery stenosis. In the Women's Health Initiative Hormone Replacement Trial (WHI-HRT) which includes postmenopausal women with an intact uterus taking ERT plus progestin and those without a uterus taking only ERT (6,7), a small increase in the number of myocardial infarctions, strokes and thromboembolism was noted in women taking active hormones compared to the placebo group. Along with HERS and ERA, WHI-HRT was the third trial to suggest that ERT is not cardioprotective in postmenopausal women with CHD and may actually increase thromboembolism and CHD events [all used Prempro, the worst of HRTs, which consists of Premarin and MPA]. Several hypotheses have been advanced to explain these unexpected findings. The most widely accepted notion is that thrombosis may be limited to a subset of women on estrogen who may be increasingly susceptible to thrombosis because of confounding risk factors, i.e., genetic mutations (8-11) in thrombogenic factors (factor V Leiden, prothrombin and plasminogen activator inhibitor gene mutations). Premarin (a brand of conjugated equine estrogen mixture marketed by Wyeth/Ayerst Labs, Radnor, PA, USA) is the estrogen used in all major clinical trials. To date, the exact composition of Premarin is not known. Recently, another brand of conjugated estrogen called Cenestin (containing 10 estrogens in a known composition marketed by Duramed Pharmaceuticals) has received approval for the treatment of menopausal symptoms (12). Despite these concerns about thrombosis, a significant portion of postmenopausal women in the United States continue to take ERT for relief of menopausal symptoms and potential benefits in terms of osteoporosis and cardiovascular diseases. In terms of cardioprotection, studies continue to document improvements in risk factors related to heart disease (2,3,13). Some of these studies are discussed below.

Estrogen and plasma lipids

Considerable data are available that document an increase in HDL and a reduction of LDL cholesterol following estrogen therapy (14). Studies have clearly established that estrogen decreases total plasma cholesterol (15) and increases or maintains plasma triglyceride levels (15-17). With the addition of progestin, plasma total cholesterol, LDL cholesterol and triglyceride levels decrease (16-18). The addition of progestin, however, slightly blunts the increase in HDL levels (16-18). HDL2 levels are increased with estrogen, but changes in HDL3 have been inconsistent (17,18). Estrogen with or without progestin significantly lowered plasma lipoprotein(a) levels (19).

Estrogens as antioxidants

Recent studies have documented that estrogens are potent antioxidants and decrease LDL oxidation in vitro andin vivo (3,20). Although earlier studies have used pharmacological concentrations of estrogens to document antioxidant activity, recently it has been shown that 17▀-estradiol is active even at physiological concentrations (21). Furthermore, the potency of catechol estrogens is far greater than that of parent estrogens (22). Studies on the mechanism of estrogen antioxidant effects have shown that estrogens strongly inhibit superoxide formation with minor effects on hydrogen peroxide and hydroxyl radical formation (23). While estrogens decrease lipid peroxidation and formation of reactive oxygen species (23), androgens and progestins increase oxidative stress parameters (24). Clinical studies on humans using E2-based preparations have clearly shown decreased LDL oxidation (25,26), while other studies using conjugated estrogens have yielded conflicting results (27,28). Whether these differences are due to different estrogen preparations or time frames is not clear at this time.

Estrogen and vascular tone

Currently, there is a strong interest in the role of estrogens in mediating vascular tone and response to vasoactive agents. Studies have documented that E2 can induce relaxation of coronary arteries, reverse acetylcholine-induced vasoconstriction and improve exercise-induced myocardial ischemia in women with coronary artery disease (29-32). Collins et al. (33) showed that E2 decreases acetylcholine-induced coronary artery responses only in women, but not in men. These vasodilatory effects of estrogen are largely believed to be mediated by increased synthesis and release of nitric oxide, a potent relaxant of vascular smooth muscle (34). Short-term E2 treatment significantly increased plasma nitric oxide levels in postmenopausal women (35). Synthesis and release of nitric oxide in cultured endothelial cells are increased significantly by estrogens (36,37) and inhibited by androgens (37). Some investigators have been able to demonstrate (38) increased expression of endothelial nitric oxide synthase in women treated with estrogens. The effects of estrogens on nitric oxide synthesis is believed to be manifested by rapid non-genomic (without changes in gene expression) effects (38,39). Elucidation of this phenomenon has indicated that the non-genomic effects may still be modulated by estrogen receptors and the readers are referred to an excellent review of this topic by Mendelsohn and Karas (39).

Other mechanisms of estrogen action

Some of the other mechanisms responsible for estrogen-mediated cardioprotection include increases in vascular prostacyclin synthesis (40), inhibition of aortic smooth muscle cell proliferation (41) and decreases in hemostatic factors (42,43) like fibrinogen and plasminogen activator inhibitor-1. The expression of vascular cell adhesion molecule, a chemotactic factor produced by endothelial cells that attracts monocytes (44), is also inhibited by estrogens (45) and stimulated by androgens and progestins (46). The readers are referred to a critical review by Farhat et al. (47) on some of these mechanisms.

Role of estrogen receptors

Recent research has provided a great deal of information on the mechanisms involved in the intracellular binding of estrogens to estrogen receptors (a and ▀), translocation to the nucleus and the occurrence of genomic effects upon binding to estrogen response elements (48-50). However, the significance of these two receptors in the manifestation of the cardio-protective effect of estrogen is still open to question since mice lacking both of these receptors continue to demonstrate inhibition of intimal proliferation after vascular injury (51). The distribution of these receptors in vascular and other tissues and their interactions with estrogens and anti-estrogens are beyond the scope of this article and have been covered in some excellent recent reviews (52). The carcinogenic effect of exogenous estrogens either by estrogen receptor activation and cell proliferation (53) or by DNA adduct formation by metabolites of catechol estrogens (54) in breast tissues has been of much concern in postmenopausal women. There is strong evidence suggesting that long-term estrogen use increases the risk for endometrial and breast cancer in women on estrogen therapy (55,56). Consequently there is a lot of interest in developing "designer estrogens" that do not have adverse effects on breast and endometrium, yet retain their beneficial effects on the bone and cardiovascular system. [Other studies fail to find this see Breast Cancer Res Treat. 2008 January; 107(1): 103–111]

Recently discovered selective estrogen receptor modulators seem to have no estrogen agonistic effects on breast and endometrial tissue (57), but their long-term cardiovascular benefits are still being assessed.

Significance of differential delivery of estrogens

Therefore, considerable attention has been focused on targeting estrogens to desired tissues (ex: vascular tissue or site of atherosclerosis, bone, etc.). Our laboratory has been interested in achieving differential effects of estrogens by differential delivery to cells. During studies exploring this possibility, we have shown (58) that a significant fraction of 17▀-estradiol (<10%) is associated with lipoproteins (predominantly with HDL), where it can be subsequently esterified and transferred to LDL (59,60). These steps also appear to be important in the manifestation of the antioxidant effect of estrogens (61). Interestingly, increasing hydrophobicity of the estrogen molecule (by esterification) increases its association with LDL (61,62), providing an opportunity to target estrogen derivatives complexed with native or modified LDL to vascular tissues. Future research should be directed at targeting estrogens to specific tissues without undesirable side effects.


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Acknowledgments Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/back.gif

The author is indebted to many colleagues who contributed significantly to some of these studies.


Correspondence and Footnotes Description: http://www.scielo.br/img/fbpe/bjmbr/v35n3/back.gif

Address for correspondence: M.T.R. Subbiah, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Medical Center, M.L.547, 234 Bethesda Ave, Cincinnati, OH 45267, USA. Fax: +1-513-221-1891. E-mail: ravi.subbiah@uc.edu

Presented at the XVI Annual Meeting of the FederašŃo de Sociedades de Biologia Experimental, Caxambu, MG, Brazil, August 29 - September 1, 2001. Research supported by the National Heart, Lung and Blood Institute (No. HL-50881). Received December 10, 2001. Accepted January 22, 2002.

 

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*  Oxidative damage is the key cause for the development of atherosclerosis http://healthfully.org/heart/id15.html

 

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Early HRT Use Linked to Reduced Risk of Alzheimer's Disease, All-Cause Dementia

All professional organizations receive significant funding from Big PhARMA and their performances prove that they go along with the agenda of their major donor.  The below article is such a case, for it does not attempt to set the record straight on types of estrogen, calls a 30% statistically not significant, and is slanted in a way to not offend their major donor.  It also should be noted that the earlier studies with few exception do not separate the different types of HRTs--jk

Medscape Caroline Cassels http://www.medscape.com/viewarticle/556106

May 4, 2007 (Boston) — New research from the Women's Health Initiative Memory Study (WHIMS) links use of hormone replacement therapy (HRT) before the age of 65 years to a reduced risk of all-cause dementia and Alzheimer's disease (AD) in women.

However, investigators warn these findings should be interpreted with caution and, at this point, have no clinical implications or indicate a need to modify current HRT guidelines.

Here at the American Academy of Neurology 59th Annual Meeting, researchers presented an analysis that showed early HRT use was associated with a 46% overall reduction in dementia risk and a 64% reduction in AD {prior to WHI study}.

"These findings are observational and have implications in terms of informing some of the research that needs to be done to determine the long-term cognitive outcomes of early HRT usage. But they do not inform clinical practice," said Victor Henderson, MD, from Stanford University in Palo Alto, California.

"The current recommendations to use hormone replacement therapy for the treatment of moderate to severe vasomotor symptoms associated with menopause at low doses and for a shorter duration are still appropriate," he added.

HRT Doubled Dementia Risk in Older Women

WHIMS is an ancillary study of the Women's Health Initiative (WHI), a large randomized, placebo-controlled trial designed to look at the impact of estrogen alone or estrogen plus progestin (E + P) on a number of health outcomes, including breast cancer and cardiovascular disease, in postmenopausal women with and without hysterectomy.

In 2002, the WHI was halted prematurely because preliminary results showed individuals receiving active treatment had an increased risk for breast cancer and cardiovascular disease compared with placebo.

Similarly, WHIMS included 2 studies that looked at cognitive outcomes and HRT in women over 65 years old. The first included approximately 4000 subjects who received E + P vs placebo, while the second study compared treatment with estrogen alone vs placebo in about 3000 women. At an average 5-year follow-up, both the E + P and the estrogen-alone trials showed conjugated estrogens, with or without progesterone, increased dementia risk when therapy was initiated after age 65 years. In the E + P trial the risk doubled, while in the estrogen-alone trial there was about a 50% increased risk.

Dr. Henderson noted that prior hormone therapy use during these trials did not influence the results of on-trial treatment. "Adverse outcomes applied to both women who had used hormones in the past and those who didn't," he said.

Cognitive Impact in Younger Women Unclear

However, he added, the relationship between HRT use and AD and dementia in younger postmenopausal women subjects remained unclear.

To better understand this relationship, investigators analyzed data provided by 7153 WHIMS participants who provided information on prior hormone exposure at initial study enrollment.

Subjects included women aged 65 to 79 years without dementia. In total, there were 2228 in the prior-users group and 4925 subjects reporting no prior use. The study's primary outcomes were baseline modified Mini-Mental State Examination (MMSE) and incident dementia.

According to Dr. Henderson, there were some differences between prior HRT users and nonusers. Those who reported past HRT use tended to be slightly older, have a higher BMI, and, although the numbers were small, had a slightly increased history of stroke and transient ischemic attack (TIA).

The study's final analysis was based on 106 women who developed dementia during the WHIMS follow-up period — 22 of whom reported prior HRT use and 84 with no HRT history before age 65 years.

Reduction in All-Cause Dementia

The results suggest the overall reduction in risk for all-cause dementia in women who took HRT before age 65 years was about 46%, which was statistically significant, said Dr. Henderson. For AD alone, the reduction in incidence was 64%. For other causes of dementia, it was approximately 30%, a result that was not statistically significant.

In the estrogen-alone study, average baseline MMSE scores were 94.95 for prior HRT users vs 94.93 for nonusers. However, this was not the case in the E + P trial. Although this finding in the estrogen-alone group was statistically significant and tended to favor prior HRT users, it is unlikely to be clinically relevant, said Dr. Henderson.

If, in fact, the protective effect of early HRT use is real, there is no indication from this study of optimal age of initiation or duration of therapy, he said.

Intriguing Results

Asked to comment on the results, Kristine Yaffe, MD, chief of geriatric psychiatry at the University of California, San Francisco–affiliated Veterans Affairs Medical Center, said the area of late cognitive outcomes related to early HRT use

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