… A RESEARCH STATES:  "I think that it borders on a tragedy that Premarin and Provera were chosen as the only HRT treatments."   {AS JK STATED ABOVE IT IS THE PROSTOGLANDIN in Provera & Premarin that caused the serious side effects}   Another researcher finds that hat Provera--and no other progestin--blocks the mechanisms that allow estrogen to fight the brain's immune response to Alzheimer's. This immune response wears away at brain cells and causes them to leak neurotransmitters such as glutamate, which overloads and kills neurons. "It's basically as if someone were to open your mouth and shove down gallons" of soft drink, Brinton explains. "It's caustic, and you can't metabolize it enough."

{After the usual journalistic waffling, the Scientific American articles gets to the issue}  For many scientists, a critical question yet remains: To what extent do the results of the initiative study apply to other forms of hormone replacement? "We cannot be sure whether other hormone combinations will have the same effects," Rossouw cautions, "but in my opinion we should assume they do until proven otherwise." But neuroendocrinologist Bruce S. McEwen of the Rockefeller University is unequivocally critical of the study: "I think that it borders on a tragedy that Premarin and Provera were chosen as the only HRT treatments."

A growing number of researchers believe that Provera is a poor substitute for progesterone. For example, medroxyprogesterone will bind in the breasts to progesterone receptors, which causes breast cells to divide after puberty and during the menstrual cycle, and also to glucocorticoid receptors, which causes cell division during pregnancy. This double-barreled assault on breast cells, explains C. Dominique Toran-Allerand, a developmental neurobiologist at Columbia University, probably led to the high rates of breast cancer in the study. "With Provera you are activating two receptors involved with cell division in the breast," she says, "and that's the culprit, not estrogen."

HORMONE HYSTERIA:  In addition, recent research shows that Provera interferes with estrogen's ability to prevent memory loss and dementia. "Estrogen is able to protect neurons against toxic assaults that are associated with Alzheimer's disease," notes Roberta Diaz Brinton, a neuroscientist at the University of Southern California. Using in vitro studies of several types of progestin, she found that Provera--and no other progestin--blocks the mechanisms that allow estrogen to fight the brain's immune response to Alzheimer's. This immune response wears away at brain cells and causes them to leak neurotransmitters such as glutamate, which overloads and kills neurons. "It's basically as if someone were to open your mouth and shove down gallons" of soft drink, Brinton explains. "It's caustic, and you can't metabolize it enough."

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Past long-term estrogen use decreases Alzheimer’s disease in older women (83% for over 10 years)

December 2002 report of NAMS (North American Menopause Society)

Zandi PP, Carlson MC, Plassman BL, et al, for the Cache County Memory Study Investigators. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County study. JAMA 2002;288:2123-2129.

Use of hormone therapy is associated with a reduced risk of Alzheimers disease (AD), especially use for longer than 10 years, according to results from this prospective observation al study conducted in Cache County (Logan, Utah). A total of 1,889 women (mean age, 74.5 years) were enrolled. A similarly aged group of men (n = 1,357) served as controls. History of hormone therapy use (either estrogen alone or estrogen plus a progestogen), as well as intakes of calcium and multivitamin supplements, were assessed at baseline. After 3 years of follow-up, 88 women (4.7%) and 35 men (2.6%) had developed AD. Women aged 80 and older had more than twice the rate of AD as men of that age (hazard ratio [HR], 2.11; 95% CI, 1.22-3.86). Overall, hormone therapy significantly reduced the risk of AD by 41% compared with nonusers (95% CI, 0.36-0.96). Hormone use for at least 10 years resulted in a 69% reduction in risk (95% CI, 0.17-0.86), which was statistically the same as the risk for matched males. When the results were assessed by current and former hormone use, current use (72% unopposed estrogen) was not associated with decreased AD risk unless the duration of treatment exceeded 10 years. For former users, 3 or more years of use significantly reduced the AD risk, with more than 10 years use reducing the risk by 83% (95% CI, 0.01-0.80). No similar effects were seen with either calcium or multivitamin use.

NOTE:  the results are based taking the best combination, other studies using different combinations obtain lower results and those with Prempro no benefit. A earlier (1999) NAMS meta-study, not separating types of HRT or duration of usage found a 29% reduction--jk. 

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Molecualr Pharmacology, April 1, 1997 vol. 51, no. 4, 535-541

Neuroprotection against Oxidative Stress by Estrogens: Structure-Activity Relationship

Abstract

Oxidative stress-induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases; one such ailment is Alzheimer’s disease. Using the Alzheimer’s disease-associated amyloid β protein, glutamate, hydrogen peroxide, and buthionine sulfoximine, we investigated the neuroprotective potential of estrogen against oxidative stress-induced cell death. We show that 17-β-estradiol, its nonestrogenic stereoisomer, 17-α-estradiol, and some estradiol derivatives can prevent intracellular peroxide accumulation and, ultimately, the degeneration of primary neurons, clonal hippocampal cells, and cells in organotypic hippocampal slices. The neuroprotective antioxidant activity of estrogens is dependent on the presence of the hydroxyl group in the C3 position on the A ring of the steroid molecule but is independent of an activation of estrogen receptors.

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8% Reduced Risk of Thrombosis with Esterfied Estrogen Only

Esterified Estrogens and Conjugated Equine Estrogens and the Risk of Venous Thrombosis

JAMA (the Journal of the American Medical association) 2004;292(13):1581-1587. doi: 10.1001/jama.292.13.1581

At http://jama.ama-assn.org/content/292/13/1581.abstract

1. Nicholas L. Smith, PhD; Susan R. Heckbert, MD, PhD;  Rozenn N. Lemaitre, PhD; Alex P. Reiner, MD, MPH;
2. Thomas Lumley, PhD; Noel S. Weiss, MD, DrPH; Eric B. Larson, MD, MPH; Frits R. Rosendaal, MD;
3. Bruce M. Psaty, MD, PhD

1. Corresponding Author: Nicholas L. Smith, PhD, Cardiovascular Health Research Unit, 1730 Minor Ave, Suite 1360, Seattle, WA 98101 (nlsmith@u.washington.edu).

Abstract

Context:  Clinical trial evidence indicates that estrogen therapy with or without progestins increases venous thrombotic risk. The findings from these trials, which used oral conjugated equine estrogens, may not be generalizable to other estrogen compounds.

Objective:  To compare risk of venous thrombosis among esterified estrogen users, conjugated equine estrogen users, and nonusers.

Design, Setting, and Participants  This population-based, case-control study was conducted at a large health maintenance organization in Washington State. Cases were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first venous thrombosis between January 1995 and December 2001 and controls were matched on age, hypertension status, and calendar year.

Main Outcome Measure:  Risk of first venous thrombosis in relation to current use of esterified or conjugated equine estrogens, with or without concomitant progestin. Current use was defined as use at thrombotic event for cases and a comparable reference date for controls.

Results:  Five hundred eighty-six incident venous thrombosis cases and 2268 controls were identified. Compared with women not currently using hormones, current users of esterified estrogen had no increase in venous thrombotic risk (odds ratio [OR], 0.92*; 95% confidence interval [CI], 0.69-1.22). In contrast, women currently taking conjugated equine estrogen had an elevated risk (OR, 1.65; 95% CI, 1.24-2.19). When analyses were restricted to estrogen users, current users of conjugated equine estrogen had a higher risk than current users of esterified estrogen (OR, 1.78; 95% CI, 1.11-2.84). Among conjugated equine estrogen users, increasing daily dose was associated with increased risk (trend P value   = .02). Among all estrogen users, concomitant progestin use was associated with increased risk compared with use of estrogen alone (OR, 1.60; 95% CI, 1.13-2.26).  * Not “no increase” but rather reduces 8%--jk.

Conclusion:  Our finding that conjugated equine estrogen but not esterified estrogen was associated with venous thrombotic risk needs to be replicated and may have implications for the choice of hormones in perimenopausal and postmenopausal women.

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Over the short period of 2 years there was a 32% reduction in MI for the use of unopposed estrogen and progestins.  Prempro however does not reduce MI.

The Risk of Myocardial Infarction Associated With the Combined Use of Estrogens and Progestins in Postmenopausal Women

Bruce M. Psaty, MD, PhD; Susan R. Heckbert, MD, PhD; David Atkins, MD, MPH; Rozenn Lemaitre, PhD; Thomas D. Koepsell, MD, MPH; Patricia W. Wahl, PhD; David S. Siscovick, MD, MPH; Edward H. Wagner, MD, MPH

Arch Intern Med. 1994;154(12):1333-1339.

Abstract

Background
While observational studies have suggested that unopposed estrogens reduce the incidence of coronary disease in postmenopausal women, there are few data on the effect of combined therapy with estrogens and progestins—a regimen adopted in recent years to minimize the risk of endometrial hyperplasia and cancer. In clinical trials, the addition of progestins has an adverse effect on serum lipid levels, and these lipid effects have raised the question of whether combined estrogen-progestin therapy increases the risk of coronary disease compared with the use of estrogen alone. {Progesterone, an alternative does not effect serum lipids, etc.--jk}

Methods
We conducted a population-based, case-control study among enrollees of Group Health Cooperative of Puget Sound. Cases were postmenopausal women who sustained an incident fatal or nonfatal myocardial infarction in 1986 through 1990. Controls were a stratified random sample of female Group Health Cooperative enrollees frequency matched to the cases by age and calendar year. We reviewed the medical records of the 502 cases and 1193 controls and conducted brief telephone interviews with consenting survivors. The health maintenance organization's computerized pharmacy database was used to ascertain the use of postmenopausal hormones. For the primary analysis of current use, we classified women into one of three groups: (1) nonusers of hormones; (2) users of estrogens alone; or (3) users of combined therapy including both estrogens and progestins. Each group of hormone users was compared with nonusers.

Results
After adjustment for potential confounding factors, the risk ratio of myocardial infarction associated with current use of estrogens alone was 0.69 (95% confidence interval, 0.47 to 1.02); and the risk ratio of myocardial infarction associated with current use of combined therapy was 0.68 (95% confidence interval, 0.38 to 1.22). Duration of combined-therapy use was relatively short, averaging less than 2 years in cases and controls.

Conclusions
In this case-control study, the reduced risk of myocardial infarction associated with the use of estrogens alone was consistent with previous observational studies. Although the 95% confidence interval only excluded a risk above 1.22, the current use of combined therapy was not associated with an adverse effect on the incidence of myocardial infarction in postmenopausal women.

(Arch Intern Med. 1994;154:1333-1339)

In Conn’s Current Therapy (2002), “ Epidemiologic studies attest to about a 50% risk reduction in CHD events and Mortality among current users of estrogen” at 1083. 

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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 Ribeirão 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.     

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Esterified Estrogen and Progesterone poses no breast cancer risk*

Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study

HAL Archives Ouvertes--France-- Published online 2007 February 27. doi: 10.1007/s10549-007-9523-x.  Breast Cancer Res Treat. Author manuscript; available in PMC 2008 January 31.

Published in final edited form as:

Breast Cancer Res Treat. 2008 January; 107(1): 103–111.

Agnès Fournier,¹ Franco Berrino,² and Françoise Clavel-Chapelon^1*

Abstract

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.

*  Even the forms of HRT which case a rise in incidents, they do so not by causing but by stimulating the growth.  Thus when HRT is discontinued the rate falls back to normal, a thing which wouldn’t occur if these drugs were carcinogenic. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

Endocrinology, doi:10.1210/en.2006-0495, Endocrinology Vol 147, No. 11 5303-5313, 2006 copyright by the Endocrine Society

Dose and Temporal Pattern of Estrogen Exposure Determines Neuroprotective Outcome in Hippocampal Neurons: Therapeutic Implications

 To address controversies of estrogen therapy, in vitro models of perimenopause and prevention vs. treatment modes of 17ß-estradiol (E₂) exposure were developed and used to assess the neuroprotective efficacy of E₂ against ß-amyloid-1–42 (Aß_1–42)-induced neurodegeneration in rat primary hippocampal neurons. Low E₂ (10 ng/ml) exposure exerted neuroprotection in each of the perimenopausal temporal patterns, acute, continuous, and intermittent. In contrast, high E₂ (200 ng/ml) was ineffective at inducing neuroprotection regardless of temporal pattern of exposure. Although high E₂ alone was not toxic, neurons treated with high-dose E₂ resulted in greater Aß_1–42-induced neurodegeneration. In prevention vs. treatment simulations, E₂ was most effective when present before and during Aß_1–42 insult. In contrast, E₂ treatment after Aß_1–42 exposure was ineffective in reversing Aß-induced degeneration, and exacerbated Aß_1–42-induced cell death when administered after Aß_1–42 insult. We sought to determine the mechanism by which high E₂ exacerbated Aß_1–42-induced neurodegeneration by investigating the impact of low vs. high E₂ on Aß_1–42-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E₂ significantly prevented Aß_1–42-induced rise in intracellular calcium, whereas high E₂ significantly increased intracellular calcium and did not prevent Aß_1–42-induced calcium dysregulation. Therapeutic benefit resulted only from low-dose E₂ exposure before, but not after, Aß_1–42-induced neurodegeneration. These data are relevant to impact of perimenopausal E₂ exposure on protection against neurodegenerative insults and the use of estrogen therapy to prevent vs. treat Alzheimer’s disease. Furthermore, these data are consistent with a healthy cell bias of estrogen benefit.

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Decrease in breast cancer found for the use of estrogen and progesterone compared to those who never used HRT; the same risk if estrogen and dydrogesterone, and a marked increase with estrogen and progestins such as with Prempro (NAMS study above).  This failure to consider adequately consider other combinations that that in Prempro entails that the WHI study has limited scope--jk.    

From Wikipedia  Women’s Health Initiative (WHI study) (the one used to get women off of HRT; see “Set Up to Fail” above which accuses the NIH for this development)

The Women's Health Initiative (WHI) was initiated by the National Institutes of Health (NIH) in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women. In particular, randomized controlled trials were designed and funded that address cardiovascular disease, cancer, and osteoporosis.

Study components

There are actually 4 different randomized interventions and a separate observational-only cohort in the WHI. All 4 of the randomized components overlap with each other to some extent (and a few even overlap with the observational study). The 4 interventions and their abbreviated terminology are:

Estrogen-progestin versus placebo

This phase studied estrogen, specifically conjugated equine estrogen, plus progestin (Prempro, Wyeth) compared to placebo (the "WHI-E+P" trial), among healthy postmenopausal women.

This trial found that, compared with placebo, women receiving equine estrogen plus progestin experienced:^[1]

• increased risk of myocardial infarction ("heart attack")
• increased risk of stroke
• increased risk of blood clots, including deep venous thrombosis (DVT) and pulmonary embolism (PE)
• increased risk of breast cancer
• decreased risk of colorectal cancer
• fewer fractures

The trial was ended early in 2002 when the researchers found that the subjects with estrogen plus progestin had a greater incidence of coronary heart disease, breast cancer, stroke, and pulmonary embolism than the subjects receiving placebo.^[2] Hormone replacement therapy use declined in the U.S. and around the world, followed by a decline in breast cancer.^[3]

Conjugated estrogen versus placebo

This trial studied estrogen, specifically conjugated equine estrogen (Premarin, Wyeth), alone versus placebo (the "WHI-CEE" trial) in women with prior hysterectomy.

The trial was conducted among women with hysterectomy so that estrogen could be administered without a progestin. In women with a uterus, a progestin is needed to counteract the risk of endometrial cancer posed by unopposed estrogen.

Major results of this study were that, compared with placebo, women receiving estrogen alone experienced:^[1]

• no difference in risk for myocardial infarction
• an increased risk of stroke
• an increased risk of blood clots
• an uncertain effect on breast cancer risk
• no difference in risk for colorectal cancer
• a reduced risk of fracture
• the claims of increased risk of stroke and blood clots does not hold up with esterifed estrogen--jk

Calcium and vitamin D versus placebo

This trial compared calcium plus vitamin D versus placebo ("WHI-CalcVitD"). This had 2 major papers arise from it in NEJM 2006, and one in May 2007 in the Archives of Internal Medicine [1]:

• CRC endpoint
• Fracture endpoint

Non-intervention cohort

The non-interventional observational cohort study ("WHI-OS") observed 93,000 women drawn from the same national clinical coordinating centers (many epidemiology studies conducted within this observational component of the WHI).

The WHI Postmenopausal Hormone Therapy Trials were part of the effort to address the high risk of cardiovascular disease in older women. By the early 1990s, many physicians had come to interpret results from previous clinical trials and studies using experimental animals as indicating that administration of an estrogen supplement to postmenopausal women would lower the incidence of cardiovascular disease. Two hormone clinical trials were designed and conducted:

The estrogen that was administered in the WHI studies was conjugated equine estrogen (CEE). This consists of a mixture of estrogens isolated from horse urine (Premarin). The CEE was administered orally. Both studies were randomized, placebo-controlled studies. Half the women were given an inactive placebo rather than hormone(s). Both studies were terminated early because a reduction in cardiovascular disease was not observed for most women and some women had dangerous side-effects. In particular, an increased risk of dangerous blood clotting is associated with oral administration of CEE. A review of the observational and WHI estrogen trial results describes potential explanations for the conflicting results.

In addition, co-administration of MPA (medroxyprogesterone acetate, a type of progestin) with CEE was associated with a slightly increased risk of breast cancer. Some benefits of using an estrogen supplement such as reduced risk of bone fractures were confirmed by these studies. However, for the older postmenopausal women who were recruited for this study, the undesirable side-effects of treatment generally were greater than the health benefits. Based on the results of these studies, CEE and MPA are no longer given to women in order to try to prevent cardiovascular disease in older women. Younger postmenopausal women seeking relief from conditions such as hot flashes, sleep disturbance and urinary/vaginal atrophy are still candidates for hormone replacement therapy. Alternatives to orally administered CEE and MPA are being increasingly used by women since the termination of the WHI studies. For example, other forms of estrogen (such as esterified estrogens) or topical administration of estradiol may reduce the risk of blood clotting compared to that for oral CEE.^[4]

Finally, the low fat dietary pattern trial of the WHI yielded conflicting and controversial results. However, the WHI trial has been argued as unnecessary by many scientists, who already knew a full decade ago that total fat intake is not related to cardiovascular risk nor postmenopausal breast cancer risk.

WIKIPEDIA ON HRT:

According to a 2007 presentation at an American Academy of Neurology meeting,^[19] hormone therapy taken soon after menopause may help protect against dementia, even though it raises the risk of mental decline in women who do not take the drugs until they are older. Dementia risk was 1% in women who started HRT early, and 1.7% in women who didn't, (e.g. women who didn't take it seem to have had—on average—a 70% higher relative risk of dementia). This is consistent with research that hormone therapy improves executive and attention processes in postmenopausal women.^[20] It is also supported by research upon monkeys that were given ovariectomies to imitate the effect of menopause and then estrogen therapies. This showed  replacement treated compared to nontreated monkeys had long term improved prefrontal cortex executive abilities on the Wisconsin card sort task.^[21]

Another recent randomized controlled trial found HRT may actually prevent the development of heart disease and reduce the incidence of heart attack in women between 50 and 59, but not for older women. The mechanism may have something to do with the contradictory effects of increasing propensity for clotting, versus improving both "good" and "bad" cholesterol concentrations in the blood (which would have a protective effect). Follow-up studies are being performed which are intended to confirm these findings. The increased risk of breast cancer remains.^[22]

The adverse cardiovascular outcomes may only apply to oral dosing with the progestin and equine estrogens in Prempro, while other types of HRT such as topical estradiol and estriol may not produce the same risks. Results from other studies suggest that when estrogen is administered orally, liver function is altered and the risk of blood clots is increased.^[4]

A recent large well-designed randomized controlled trial recently showed that increased breast cancer risk applies only to those women who take progesterone analogues (as was done in the WHI) but not to those taking progesterone itself ^[23]    

At http://healthfully.org/fhr/ there is a collection of over 20 journal articles supporting the positive claims made about the right formulation of HRT at the beginning of this paper.  Most of these articles are before 1999 (a guess at when Big PhARMA decided to go after HRT); however, based on the WHI study this date would be pushed back to 1990, since WHI study began in 1991.  Most of the population studies, unfortunate group the various formulations of HRT together thus were not included in this collection on HRT.