Bioidentical Hormone Estrogen Prevents Heart Disease

Estrogen Prevents Heart Disease Bioidentical Hormones

Estrogen Prevents Heart Disease

by Jeffrey Dach MD

The “Flip Flop” on Estrogen and Heart Disease

Medical science has done a “Flip-Flop” on estrogen and coronary heart disease.  Before 2003, forty observational studies had convinced mainstream doctors that estrogen prevents heart disease in women.   It was considered unethical not to offer HRT (hormone replacement therapy)  to post-menopausal women, and three mainstream medical groups published guidelines saying so.  It was believed that ovarian hormone production (estrogen) in the pre-menopausal women bestowed protection from coronary heart disease (CHD), and likewise, estrogen replacement in post-menopausal women prevented coronary artery disease (CAD).

2002 WHI Study with Premarin and MedroxyProgesterone (Prem-Pro)

The tables were turned in 2002,  when the Women’s Health Initiative (WHI) showed increased heart disease in the Prempro Treated Group, for which the study was terminated  early. (17)  The failure of the WHI Trial, RCT (randomized controlled study), to show any cardiac benefit for the Prem-Pro users was the final straw, arriving on the shirt-tails of a number of RCT studies in the 1990’s, such as the HERS trial,  all expecting the same cardio-protection shown in observational and animal studies.  Yet, these RCT’s were an utter disappointment, and failed to show reduction in heart disease in the hormone users. (22)  The question is : “Why did these studies fail?”  Here is the answer (below):

The Wrong Hormones and the Wrong Age Group

The WHI First-Arm, the HERS study and other RCT’s (randomized controlled trials) in the 1990’s  used the wrong hormones, the synthetic “progestin”,  medroxyprogesterone.  They also used the wrong age group, “older women” in their 60’s , fifteen years out from the menopausal transition.

Dr Barrett-Conner 2003 – Estrogen is a Failure !!!

In a 2003 publication, Dr Barrett-Conner laments the failure of estrogen to prevent coronary artery disease (CHD) in post-menopausal women:  Dr Barrett-Conner’s dramatic quote:

The failure to find cardioprotective effects in any of the several clinical trials with CHD outcomes offers little hope that postmenopausal HT (Hormone Replacement) will prevent heart disease. The results, unexpected and unwelcome, are nonetheless definitive and are likely to extend beyond the studied treatment regimens. (1)

Of course, the above comment by Dr. Barrett-Conner is completely wrong, as you will see below.

2011 – Massive Flip-Flop, Estrogen Is Indeed Cardio-Protective

The 2011 JAMA report of the 11 year follow-up of the Second Arm (Premarin-only) of the WHI (Women’s Health Initiative), clearly showed that estrogen reduces mortality from heart disease, reduces heart attacks and reduces all cause mortality (see data below) (15,16)

However, protection was conferred only on the 50-60 year age group, and not on the older women, after 10-20 years of hormone deficiency.   In addition, this protection was lost or reduced when a synthetic progestin, medroxyprogesterone was added to the RT cocktail.

Here is the DATA from the 11 year follow up JAMA WHI publication (15)

This is the Second Arm Study which used Premarin Alone in women after hysterectomy.

Events by Group
(years of age)      Coronary Artery Disease
CHD                    Hazard Ratio
50-59 yrs…………0.59
60-69 yrs…………1.0
70-79 yrs…………1.06

Total MI             Hazard Ratio
(Myocardial Infarction)
50-59 yrs…………0.54
60-69 yrs…………1.05
70-79 yrs…………1.23

All-Cause Mortality Hazard Ratio
50-59 yrs…………0.73
60-69 yrs…………1.04
70-79 yrs…………1.12

Invasive Breast Cancer Hazard Ratio
50-59 yrs………...0.80
60-69 yrs…………0.73
70-79 yrs…………0.81

Notice that for the “younger” age group (age 50-60 yrs), HRT with Premarin-alone provided an  astounding 41% reduction in coronary artery disease, 46% reduction in myocardial infarctions, and 27 % reduction in all cause mortality.  In addition, there is a 20-30% reduction in breast cancer.  When one lumps all the age groups together, the benefit is NULL.  However, when one looks at the 50-60 age group, starting hormone replacement immediately after hormone decline of menopause, the benefits are striking.

The Explanation- Preventing a Degenerative Disease Doesn’t Work if You Already Have It

The explanation for the Flip-Flop is actually quite simple.  As Mark Houston MD so aptly describes in his new book, coronary artery disease is a chronic degenerative disease caused by inflammation, preventable when preventive measures are started early, before irreversible tissue damage. Once the degenerative disease has a chance to develop, irreversible tissue damage has ocurred and the preventive measure is ineffective. This is true for  osteoarthritis, and coronary atherosclerosis, both degenerative diseases.

This explains why estrogen is effective in preventing atherosclerotic coronary artery disease in the 50-60 year age group, if started immediately after menopause.  And, this also explains why HRT (hormone replacement therapy) is ineffective when introduced ten or twenty years later, after enough time has elapsed to develop atherosclerotic coronary artery disease. Although considered irreversible, coronary artery disease may be reversed at least in part by our Calcium Score Protocol described in my book, Heart Book by Jeffrey Dach MD. Medical Muse Press; First Edition (August 2, 2018).

Above image: Surgeons performing cardiac bypass operation on patient with coronary artery disease, courtesy of Wikimedia Commons. public domain. NIH.

23 RCT’s Re-Examined – Behold a Benefit for Younger Post-Menopause

In 2006, Drs. Shelley R. Salpeter,and Judith Walsh, reviewed 23 RCT’s (randomized controlled trials) of hormone replacement from the 1990’s and teased out the data for the younger women started early on HRT immediately after menopause transition, the authors found a 30-40% reduction in cardiovascular disease, essentially duplicating the data from the WHI study estrogen-alone arm, JAMA 2004. (21)

The Take Home Message:Don’t Wait

The take home message for a women entering menopause is : “Don’t Wait” to start bioidentical hormone replacement immediately upon onset of menopausal symptoms. Post-menopausal estrogen deficiency is a health risk leading to chronic degenerative diseases: coronary atherosclerosis, osteoarthritis, osteoporosis , cognitive impairment, cognitive dysfunction, as well as generalized inflammation. (44-50)

Doctor Sangeta Pati’s often quoted remark:

Many people ask, how safe is it “really”, to do hormone replacement? Yet, the real question is,  How safe is it NOT TO DO hormone replacement? (41)

Two Coronary Calcium Score Studies Are Consistent with Cardio-Protection

Coronary Artery Calcium Score has emerged over the last decade as a highly sensitive and accurate imaging test for determining heart attack risk, and quantifies coronary artery plaque. The Women’s Health Initiative included two coronary calcium score studies showing striking calcium score benefits in the Premarin-alone users, but not in the Premarin-Progestin combination users.

Above left image: Photo of Vivelle-Dot by Novartis, an estrogen (estradiol) patch courtesy of Wikimedia Commons. author:Belinda Hankins Miller. CC 2.0

In 2007, Dr. JoAnn Manson’s measured calcium score at the end of the 8.7 year observation period for “younger” post-menopausal women in the 50-59 age group. This group, using estrogen-alone (Premarin or CEE, conjugated equine estrogens 0.625 mg per day) showed 60% reduction in calcium score compared to placebo users (calcium score of 83.1 vs.123).  Dr. JoAnn Manson writes:

The mean coronary-artery calcium score after trial completion was lower among women receiving estrogen (83.1) than among those receiving placebo (123.1). (18)

Reduction in Calcium Score Progression with Estrogen-Alone, Dr Budoff

In 2005, Dr. Matthew Budoff conducted a second study calcium score study from women in the WHI. This study performed two consecutive calcium scores one year apart examining progression of calcium score. For the estrogen-alone treated women, Dr. Budoff found a 9 percent annual increase in calcium score compared to 22% annual increase for placebo users. Prempro (Premarin plus medroxyprogesterone showed a 24% annual increase in the calcium score, about the same as placebo. This is highly significant because of the 2004 study by Paolo Raggi study which showed annual progression of calcium score over 15 percent is associated with high risk for heart attack, while under 15 percent annual progression is associated with good prognosis with no heart attacks in this group. (19).(42)

No Cardiovascular Benefit from Estrogen/Medroxyprogesterone Combination

In 2007, Dr. Alexander Becker in Germany studied calcium score progression over 3 years in 277 women taking premarin-progestin combination compared to matched non-users. This study showed no calcium score benefit when medroxyprogesterone is added to the estrogen. The 3 year increase in calcium score was the same for both groups, hormone users and non-users with no cardiovascular benefit in the hormone users. Thus confirming the above 2005 calcium score study by Dr. Mathew Budoff showing adding progestin to the estrogen negates the cardiovascular benefits of estrogen.  (43)

How Does Estrogen Prevent Coronary Artery Disease ?
Anti-Inflammatory Effects of Estrogen – Prevents Endothelial Dysfuction

An excellent 2009 article by Dr. Bechlioulis reviews the benefits of estrogen in preventing endothelial dysfunction, the initiating step in atherosclerosis.  Flow mediated dilatation of the brachial artery (FMD) is a handy tool to evaluate endothelial dysfunction. Studies using FMD show that estrogen deficiency is linked to endothelial dysfunction in post menopausal women, women with premature menopause, surgically induced menopause, and other groups with low estrogen levels. (20)

Estrogen is Anti-Inflammatory – Basic Science Studies

A number of basic science studies in animals and humans show that estrogen has a profound anti-inflammatory effect, and this explains much of the cardio-protection. (23-31)

Carotid plaque study from Italy – Less inflammation in the Plaque

In 2008, Dr. Raffaele Marfella from Italy conducted an elegant study of carotid artery plaques obtained from surgical specimens from post-menopausal women on HRT (hormone replacement therapy). Dr. Marfella studies the microscopic histology of the plaques looking for inflammatory markers and cells. These findings were then compared to carotid artery samples from non-hormone-user controls. In women using hormone replacement, the authors found considerable reduction of inflammatory cells and markers in the plaque material. Dr. Raffaele Marfella concludes that hormone replacement therapy inhibits inhibits the activation of nuclear factor B–dependent inflammation, responsible for plaque rupture. Dr. Raffaele Marfella writes:

this study examined the differences in inflammatory infiltration, as well as ubiquitin-proteasome activity, between asymptomatic carotid plaques of postmenopausal women with and without concomitant hormone replacement therapy. Plaques were obtained from 20 postmenopausal women treated with hormone replacement therapy (current users) and 32 nontreated women (never-users) enlisted to undergo carotid endarterectomy for extracranial high-grade (70%) internal carotid artery  stenosis. Plaques were analyzed for macrophages, T lymphocytes, human leukocyte antigen-DR cells, ubiquitinproteasome system, nuclear factor B, inhibitor of nuclear factor B, tumor necrosis factor-, nitrotyrosine, matrix metalloproteinase-9, and collagen content (immunohistochemistry and ELISA). Compared with plaques from current users, plaques from never-users had more macrophages , T lymphocytes, and human leukocyte antigen-DR cells [reactive immune cells], more ubiquitin-proteasome activity, tumor necrosis factor-, and nuclear factor B (P0.001); and more nitrotyrosine and matrix metalloproteinase-9 (P0.001), along with a lesser collagen content and inhibitor of nuclear factor B levels (P0.001). This study supports the hypothesis that hormone replacement therapy inhibits plaque ubiquitin-proteasome activity by decreasing oxidative stress generation in postmenopausal women. This effect, in turn, might contribute to plaque stabilization by inhibiting the activation of nuclear factor B–dependent inflammation, responsible for plaque rupture. (30)

Note: The ubiquitin-proteasome system is the principal degradation route of intracellular and oxidized proteins.  In human carotid plaques increased oxidative stress is associated with inhibition of the proteasome activity and accumulation of ubiquitin conjugates, particularly in symptomatic patients. (30B)

Estrogen Up-Regulates EPC’s

The Endothelial Progenitor Cell (EPC) has been recognized as an important component of cardio-protection, and estrogen upregulates the EPC’s, conferring protection post-myocardial infarction in a mouse model.   The administration of estrogen stimulates faster recovery after ischemic injury by increasing EPC’s and neo-angiogenisis (29)

Estradiol Metabolite Prevents Atherosclerosis

Dr. Bourghardt reported in Endocrinology 2007  that a metabolite of estradiol called 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient mice. This is another reason to offer bio-identical estradiol rather than Premarin as the preferred form of estrogen for HRT.  Dr. Bourghardt writes:

The anti-atherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens [such as Premarin(r)]. (32)

Drs. Howard Hodis and Wendy Mack Sum it Up (8,9,10)

The Cardio-Protection of Estrogen is best described by Drs. Howard Hodis and Wendy Mack in a series of articles from 2008 to 2011 which point out that for women in the 50-60 year age group, shortly after the onset of menopausal hormone decline, all of the RCTs (Randomized Controlled Trials ) are in agreement with observational and animal studies.  These clearly show a significant cardio-protective effect of estrogen replacement of about 40-50%.(8-10).

Drs Hodis and Mack point out that this age group and results are similar to all the preceding observational and non-human primate studies.  This 50-60 age group is called the “Window of Opportunity” for Hormonal Replacement.(1)(13-13B)

This makes sense when considering that hormonal decline of natural or surgically-induced menopause is associated with degenerative diseases such as coronary artery disease, osteoporosis , osteoarthritis , cognitive decline,  all of which are associated with increased mortality rate. (11,12,12A,12B)

Estrogen Prevents Onset of Degenerative Disease

If one considers menopause as heralding the onset of various degenerative diseases, then this explains why hormone replacement is protective in the early post-menopausal time period, and is ineffective 10 to 15 years after menopause.   This also explains why Premarin (estrogen) is dramatically successful for reducing heart disease risk in the 50-60 age group, and ineffective for the over 60 age group in the 11 year follow data for the WHI second arm.(15,16)

Avoid Synthetic Monster Hormones

In addition, it is now clear that women must avoid synthetic hormones, such as medroxyprogesterone (MPA), a “progestin” in the Prem-Pro Pill (Provera).  This synthetic monster hormone increases risk for heart attacks, coronary artery disease, and opposes the cardio-protective effects of estrogen. Around 20 observational studies show the progestin, medroxyprogesterone (MPA), increases risk for breast cancer. Natural hormones estradiol, progesterone and testosterone are the preferred choice. (51-55)

Avoid Blood Clots with Trans-Dermal Estrogen

A 2010 report by Dr. Leonard Speroff in Climacteric points out that topical estrogen is preferred over the pill form of estrogen (such as Premarin).  The transdermal route is not associated with increased blood clots since it avoids first pass through the liver. (13)

Lipitor-Statin Anti-Cholesterol Drug to Prevent Heart Disease in Women?

Many post-menopausal women come to my office for their first visit on Lipitor, Crestor, Baychol or some other statin anti-cholesterol drug intended to prevent heart disease.  In addition, these women are all “terrorized” by the drug marketing television campaigns, and are all worried and obsessed that the cholesterol is too high.  The first thing they ask me is, “what is my cholesterol”?.  The cardiologists and primary docs just go along with the ruse and hand out Lipitor to women quite freely.  Statin drugs come with horrendous adverse side effects that I see every day in my office.  To give such a drug treatment without any known benefit to out-weigh the adverse effect is a form of mistreatment and abuse which must be halted.

Dangers of Statin Drugs: What You Haven’t Been Told About Popular Cholesterol-Lowering Medicines

Dangers of Statin Drugs: What You Haven’t Been Told About Popular Cholesterol-Lowering Medicines June 14, 2004 By Sally Fallon and Mary G. Enig, PhD

 

Adverse Effects of Statin Drugs

In 2008, Dr. Beatrice Golomb summarized the adverse effects of statin drugs writing the statin drugs are mitochondrial toxins and deplete Co-Enzyme Q10 levels, causing neuropathy, myopathy, congestive heart failure, transient global amnesia, erectile dysfunction, dementia and blood sugar elevation, etc.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849981/
Golomb, Beatrice A., and Marcella A. Evans. “Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism.” American Journal of Cardiovascular Drugs 8 (2008): 373-418.

https://pubmed.ncbi.nlm.nih.gov/11818357/
Rizvi, Kash, John P. Hampson, and John N. Harvey. “Do lipid-lowering drugs cause erectile dysfunction? A systematic review.” Family practice 19.1 (2002): 95-98.

Sattar, Naveed, et al. “Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.” The Lancet 375.9716 (2010): 735-742.

https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1239335/full
Laakso, Markku, and Lilian Fernandes Silva. “Statins and risk of type 2 diabetes: mechanism and clinical implications.” Frontiers in Endocrinology 14 (2023): 1239335.

https://pubmed.ncbi.nlm.nih.gov/31030614/
Tan, Brendan, et al. “Evidence and mechanisms for statin-induced cognitive decline.” Pharmacology 12.5 (2019): 397-406.

Attardo, Silvia, et al. “Statins Neuromuscular Adverse Effects.” International journal of molecular sciences 23.15 (2022): 8364.

Langsjoen, Peter H., et al. “Statin-associated cardiomyopathy responds to statin withdrawal and administration of coenzyme Q10.” The Permanente Journal 23 (2019).

Okuyama, Harumi, et al. “Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms.” Expert review of clinical pharmacology 8.2 (2015): 189-199.

Langsjoen, Peter H., et al. “Treatment of statin adverse effects with supplemental Coenzyme Q10 and statin drug discontinuation.” Biofactors 25.1‐4 (2005): 147-152.

No Benefit For Women with Statin Drugs

The reality is that statin drugs do not reduce mortality from heart disease in women, nor do they reduce all cause mortality.   This data is summarized nicely in articles by  Dr. Dr. Judith Walsh in JAMA 2004, by Dr. Petretta 2010 Int Journal of Cardiology, and Dr Ray 2010 Archives of Int Med (38,38b,39).

Lipid Lowering with Statin Drugs Ill-Advised. In 2011, Drs. Hodis and Mack write:

Lipid-lowering therapy, predominantly with HMG-CoA reductase inhibitors (statin drugs) is the mainstay for the primary prevention of CHD in women. The cumulated data however, do not provide convincing evidence for the significant reduction of CHD with lipid-lowering therapy relative to placebo when used for primary prevention of CHD in women and there is no evidence that such therapy reduces overall mortality. (8)

The Short History of Women’s Hormone Replacement and Heart Disease

1920–1939: Estradiol synthesized (1938)

1940–1949: Premarin introduced (1942)

1983-1987 : Observational Studies on RT and Heart Disease. The first observational studies of the benefits of RT (hormone replacement) were published by Trudy Bush in 1983 and 1987 showing reduction in cardiovascular disease and total mortality in hormone users. (2,3)

1991- 50% Reduction in Mortality from Heart Disease- 11 studies.  In 1991, Dr Conner reported that 11 studies showed a 50% reduction in mortality from heart disease for post-menopausal women using estrogen alone (without a progestin).(4) She writes: “Most, but not all, studies of hormone replacement therapy in post-menopausal women show around a 50% reduction in risk of a coronary event in women using unopposed oral estrogen.”(4)

1992 Landmark Meta-Analysis- Guidelines Offer Estrogen to Prevent Heart Disease.  In 1992 Dr Deborah Grady publishes a landmark meta-analysis in the Annals of Internal Medicine, reviewing the medical literature since 1970 showing post-menopausal estrogen replacement reduces risk of heart disease in women, and reduces fracture risk as well. (5)

1992- Three Medical Organizations Endorse Estrogen Therapy to Prevent Heart Disease.  Also in 1992, three medical organizations , the American College of Physicians, the American College of Obstetrics and Gynecology and the American Heart Association proposed guidelines that all postmenopausal women should be offered estrogen hormone replacement to prevent heart disease.(5,6,7)

1995–1999  PremPro, the first combination Hormone Replacement pill is introduced,  HERS study (1998) using Prempro reports early increased heart disease risk.

2002–2003  WHI (First Arm-Using Prempro) reports increased heart disease, stroke, and breast cancer, WHI continues unopposed estrogen arm (Premarin alone Second Arm), FDA requires black box warning for all postmenopausal estrogens with or without progestin.

2003 Dr Barrett – Connor.  In 2003, Dr Barrett Conner wrote an article in JCEM summarizing the previous three decades of research on estrogen and heart disease (1). In her article, she observes:

“Women have lower risk of heart disease than men of comparable age, with roughly twice the mortality for males compared to females.” (1)

Observations suggesting estrogen is cardio-protection for women (1):
a) Heart disease is uncommon in women before the age of menopause,
b) Heart disease is more common in women who have a premature natural menopause,
c) Heart disease is more common in young women who have had both ovaries removed, and
d) Heart disease is less common in women who take hormone therapy (HRT) after menopause.

2004 – WHI Second Arm published in JAMA showing less breast cancer and less heart disease in Hormone Users (Premarin only) (15)

2011 – WHI Second Arm 11 year follow up data published showing Coronary artery disease reduced by half in “younger” 50-60 yr. women using Premarin alone without a progestin.(15,16)

Conclusion – Don’t Wait:

The cardio-protective benefits of estrogen replacement are greatest at the initiation of menopause, and health benefits diminish after the many years in which degenerative disease is allowed to progress.  The conclusion is:

DON’T WAIT to start Hormone Replacement.  The health benefits are greatest when starting hormone replacement at the initiation of menopause.

Update: see this 2012 study in BMJ: Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.BMJ 2012; 345  Conclusions:

After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.

https://www.bmj.com/content/345/bmj.e6409.abstract
Schierbeck, Louise Lind, et al. “Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.” Bmj 345 (2012).  Denmark, 1990-93.

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.

Main outcome measure The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction.

Results At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer.

Conclusions After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.

 

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Jeffrey Dach MD
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Links and References

1) Barrett-Connor, Elizabeth. “An epidemiologist looks at hormones and heart disease in women.” The Journal of Clinical Endocrinology & Metabolism 88.9 (2003): 4031-4042.

HERS used PREMPRO  – Primary Prevention

1993, HERS was the first large clinical trial specifically designed to evaluate whether estrogen plus progestin therapy reduced the risk for CHD events in postmenopausal women with established coronary disease. HERS was a multicenter randomized, double-blind, placebo-controlled trial that enrolled 2763 U.S. postmenopausal women (mean age, 67 yr); eligibility required an intact uterus and documented CHD. The HERS intervention was a single daily tablet containing CEE (0.625 mg) and MPA (2.5 mg) or placebo. The study closed a little ahead of schedule in July 1998, after an average follow-up of 4.1 yr.

Results: NO Difference

HERS results, published the same year (25), showed no overall difference in the primary CHD outcome (nonfatal MI and CHD death combined) between the HT and placebo groups. Nonfatal MI or CHD death occurred in 179 women in the hormone group and 182 women in the placebo group (relative hazard, 0.99; 95% CI, 0.81–1.22) despite significant lowering of low-density lipoprotein (LDL) and increase in HDL cholesterol in the HT group (P < 0.001).

Secondary prevention trials of HT- women with known heart disease

At the time of its publication, the most valid criticism of HERS was that it was only a single trial, possibly administering the wrong HT regimen. However, several smaller secondary prevention trials described below have also reported no benefit after HT, and some suggest harm. Several studied estrogens other than CEE and regimens without a progestin.

Papworth HT Atherosclerosis Study (PHASE).

Clarke et al. (32) reported an unblinded trial in 255 women with angiographically proven heart disease (mean age, 66 yr), who were randomly assigned to no treatment or a 17 ß-estradiol patch (2.5 mg). The patch was administered alone every 4 d to women without a uterus or, for women with a uterus, administered over 14 d, followed by four patches containing 3 mg of 17 ß-estradiol and 4 mg norethisterone.

The primary endpoint was cardiac death, proven MI, or hospitalization for unstable angina. After an average of 31 months, the data and safety monitoring board recommended early closure, based on futility. The CHD event rate for the HT group was 15.6 per 100 patient years compared with 12.6 per 100 patient years in the control group.

Estrogen in the Prevention of Reinfarction Trial (ESPRIT) (33).

In this secondary prevention trial, investigators randomly assigned 1017 women (mean age, 63 yr) who had survived a first heart attack to either 2 mg of unopposed estradiol valerate daily or placebo. After 2 yr, the frequency of reinfarction or cardiac death did not differ by treatment assignment [rate ratio, 0.99 (95% CI, 0.70–1.41)], and there was also no difference in all-cause mortality. There was no evidence of early harm.

Estrogen Replacement and Atherosclerosis (ERA).

Herrington et al. (34) randomly assigned 309 postmenopausal women (mean age, 66 yr) to receive 0.625 mg of CEE alone (for women without a uterus), CEE with 2.5 mg of MPA daily (for women with a uterus), or placebo. Women were required to have had at least one coronary stenosis of at least 30% of the luminal diameter measured by quantitative coronary angiography. After an average follow-up of 3.2 yr, 248 women had a repeat coronary artery angiogram; the mean minimal coronary artery diameters did not differ significantly by treatment group, despite significant reductions in LDL cholesterol and increases in HDL cholesterol in the women assigned to HT. Patterns were the same with unopposed estrogen or the combined regimen.

Women’s Angiographic Vitamin and Estrogen (WAVE).

In this placebo-controlled factorial design, Waters et al. (35) randomly assigned 423 postmenopausal women (mean age, 66 yr) to daily continuous combined oral CEE 0.625 mg and MPA 2.5 mg with or without vitamins E and C. Eligibility required a minimum of 15% coronary artery atherosclerosis on a baseline angiogram. After an average follow-up of 2.8 yr, a repeat coronary angiogram in 306 of these women showed somewhat greater progression in each active treatment group. In a preplanned analysis that assigned death, nonfatal MI, or stroke to the worst angiographic rank, the risk was nearly doubled in women assigned to HT compared with controls (HR, 1.9; 95% CI, 0.97–3.6), but these differences were not statistically significant.

Postmenopausal hormone replacement and carotid atherosclerosis

HERS B-mode ultrasound substudy (36).

Five clinical centers recruited 454 women from the HERS cohort who agreed to have a carotid ultrasound at baseline. After 3.8 yr, a follow-up scan was obtained from 362 women. Intimal medial thickness (IMT) increased in both HT and placebo groups, with no overall difference in the primary outcome, but there was slightly slower IMT progression at the bifurcation (one of two secondary outcomes) with P = 0.06 favoring the HT treatment (36).

Postmenopausal Hormone Replacement against Atherosclerosis (PHOREA).

Angerer et al. (37) enrolled 321 healthy women (average age, 66 yr) who had increased IMT in at least one segment of the carotid arteries. They were randomly assigned to 1 mg 17 ß-estradiol daily plus 0.025 mg gestodene for 12 d every month, or the same regimen with the same dose of gestodene taken only once every 3 months, or no HT (no placebo). The trial lasted only 48 wk, with 264 women available for a second carotid ultrasound. HT did not slow progression in the carotid arteries, despite a significant decrease in LDL cholesterol and fibrinogen levels.

The Women’s Health Initiative (WHI) (39).

Begun in 1992, WHI included a randomized double-blind placebo-controlled clinical trial designed to evaluate the effect of three separate preventive strategies (HT, diet, and calcium supplements) on disease outcomes in healthy postmenopausal women aged 50–79 yr. In one HT arm of the trial, 16,608 women who had an intact uterus were randomly assigned to receive a single daily tablet containing CEE (0.625 mg) and MPA (2.5 mg) or placebo, the same regimen used in HERS. Another 10,739 women without a uterus were randomly assigned to placebo or CEE (0.625 mg/d) without MPA. The primary outcome was fatal and nonfatal heart disease, and stopping rules were established on the basis of predicted cardiovascular benefit; harm was not expected. Breast cancer was the primary adverse outcome with stopping rules. A global risk-benefit ratio was the third primary outcome. Study completion was scheduled for 2005.

After an average of 5.2 yr, the combined estrogen-progestin arm was stopped on the advice of the DSMB, because the test statistic for invasive breast cancer exceeded the stopping boundary for the adverse event, the global index showed risks exceeding benefits, and there was no reason to expect future favorable effects on cardiovascular disease.

Only 6 wk later, after all the WHI participants had been informed, the main WHI outcomes paper was published in the Journal of the American Medical Association (39). None of the excess risks or benefits was large (all less than 10 events per 10,000 women per year) as shown in Fig. 5?. The hazard ratio for CHD was 1.29 (1.02–1.63) with 286 cases; this risk was apparent almost immediately. The hazard ratio for breast cancer was 1.26 (1.00–1.59) with 290 cases; this excess risk emerged after 4–5 yr. Increased risks of stroke (1.41; 1.07–1.85), apparent after about 2 yr, and pulmonary emboli (2.13; 1.39–3.25), which were apparent almost immediately, were also observed. In analyses adjusted for multiple outcomes and sequential monitoring, most of the adverse or beneficial effects were no longer statistically significant, but it will be recognized that this was an extremely conservative analysis. It is a common convention that primary outcomes in clinical trials (in this case heart disease, breast cancer, and global index) are interpreted without adjustment for multiple testing.

It is doubtful that the WHI cardiovascular results would have been believed at all without the HERS data. Despite WHI and the other small trials, many still doubt that HT does more harm than good. Currently, one of the most common discussion points is that the women in HERS and WHI were too old (average age, 67 and 63 yr, respectively) and already had coronary artery atherosclerosis.

In fact, the WHI data show that women between ages 50 and 60 yr had fewer cardiovascular events than women in older age groups, but the highest relative risk (Table 3?). This is expected in that younger women have little CHD, so any excess risk will stand out clearly. The higher heart disease rates in older women make any small HT-associated CHD excess less obvious.

2) Bush, Trudy L., et al. “Estrogen use and all-cause mortality: preliminary results from the Lipid Research Clinics Program Follow-Up Study.” Jama 249.7 (1983): 903-906.

The association of exogenous estrogen use and hysterectomy status with all-cause mortality was examined in 2,269 white women, aged 40 to 69 years, who had been followed up for an average of 5.6 years in the Lipid Research Clinics Program Follow-up Study. A total of 72 deaths occurred during this period. The relative risk of death in estrogen users compared with nonusers was 0.54 in gynecologically intact women, 0.34 in hysterectomized women, and 0.12 in bilaterally oophorectomized women. The risk of death in estrogen users, irrespective of hysterectomy status, was 0.37 times that in nonusers (3.4/1,000 v 9.3/1,000).

3) Bush, Trudy L., et al. “Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study.” Circulation 75.6 (1987): 1102-1109.

A cohort of 2270 white women, aged 40-69 years at baseline, were followed for an
average of 8.5 years in the Lipid Research Clinics Program Follow-up Study. There were 44 deaths due to cardiovascular disease among the 1677 nonusers of estrogens and six cardiovascular disease deaths among the 593 estrogen users. The age-adjusted relative risk (RR) of cardiovascular disease deaths in users compared with nonusers was 0.34 (95% confidence limits 0.12 to 0.81).

4) Barrett-Connor, Elizabeth, and Trudy L. Bush. “Estrogen and coronary heart disease in women.” Jama 265.14 (1991): 1861-1867.

“Most, but not all, studies of hormone replacement therapy in postmenopausal women show around a 50% reduction in risk of a coronary event in women using unopposed oral estrogen.”

5) Grady, Deborah, et al. “Hormone Therapy To Prevent Disease and Prolong Life in Postmenopausal Women.” Annals of Internal Medicine 117 (1992): 1016-1037.

6) Grady, Deborah, et al. “Guidelines for counseling postmenopausal women about preventive hormone-therapy.” Annals of internal medicine 117.12 (1992): 1038-1041.

7) Andrews, W., et al. “Guidelines for counseling women on the management of menopause.Washington, DC: Jacobs Institute of Women’s Health Expert Panel on Menopause Counseling (2000).

8) Hodis, Howard N., and Wendy J. Mack. “A “window of opportunity:” the reduction of coronary heart disease and total mortality with menopausal therapies is age-and time-dependent.Brain research 1379 (2011): 244-252.

The totality of data indicates that the “window of opportunity” for reducing coronary heart disease (CHD) and overall mortality is initiation of hormone therapy (HT) within 6 years of menopause and/or before 60 years of age.

Reduction of CHD risk and overall mortality with prolonged HT use in this subgroup of women is consistent across randomized controlled trials and observational studies. As such, HT use for 5 to 30 years in postmenopausal women who initiate HT in their 50s substantially increases quality-adjusted life-years (QALYs) by 1.5 QALYs and is highly cost-effective at $2438 per QALY gained. Cumulated randomized controlled trial results indicate a consistency along with observational data that young postmenopausal women with menopausal symptoms who use HT for long periods of time have lower rates of CHD and overall mortality than comparable postmenopausal women who do not use HT.

Lipid Lowering with Statin Drugs Ill Advised

Lipid-lowering therapy, predominantly with HMG-CoA reductase inhibitors (statins) is the mainstay for the primary prevention of CHD in women (Executive Summary, 2001; Mosca et al., 2004). The cumulated data however, do not provide convincing evidence for the significant reduction of CHD with lipid-lowering therapy relative to placebo when used for primary prevention of CHD in women and there is no evidence that such therapy reduces overall mortality (Table 4) (Walsh et al., 2004; Petretta et al., 2010). Data used to support lipid-lowering therapy for the primary prevention of CHD in women and upon which current recommendations are based are small compared with those of men (Walsh et al., 2004). Recommendations for lipid-lowering therapy in the primary prevention of CHD in women are predominantly extrapolated from data derived from men and from secondary prevention trials in women.

Meta-analyses of the cumulated RCT data for the prevention of CHD indicate that there is a sex-specific efficacy for the major therapies used for the primary prevention of CHD. Both lipid-lowering and aspirin therapy have a null effect on the primary prevention of CHD in women and no effect on overall mortality (Table 4) (Walsh et al., 2004; Petretta et al., 2010; Ridker et al., 2005; Berger et al., 2006; Ogawa et al., 2008).

In stark contrast to lipid-lowering and aspirin therapy for the primary prevention of CHD, the cumulated data across more than 2 dozen RCTs demonstrate a significant reduction in CHD and overall mortality in women who are younger than 60 years of age and within 6 years of menopause when initiating HT (Table 4) (Salpeter et al., 2004; Salpeter et al., 2006; Salpeter et al., 2009a; Salpeter et al., 2009b).

Initiation of HT in close rather than remote proximity of menopause and continued for a prolonged duration appears to be key in the full expression of the cardioprotective and reduction of overall mortality effects of HT (Hodis et al., 2003; Hodis and Mack, 2007a; Hodis and Mack, 2007b; Hodis and Mack, 2008).

Conclusion:

The totality of data indicate that the effect of postmenopausal HT on CHD and overall mortality is modified by the timing of initiation (age and time since menopause) and the duration of therapy. The greatest benefit occurs in women who initiate HT below age 60 years or within 6 years of menopause. It is this latter group of women who are in the most need of symptomatic relief of menopausal symptoms such as flushing for which estrogen remains the most effective therapy (Nelson et al., 2006). RCTs are supported by approximately 40 observational studies that also indicate that initiation of HT early in the postmenopausal period and continued for a prolonged period of time results in a significant reduction of CHD and overall mortality. Comparison of the results from RCTs, observational studies and case-control studies indicates that selection bias does not explain the consistent evidence that HT is associated with a duration- and time-dependent lowering of CHD and overall mortality.

Analyses of the subgroups of women within RCTs that resemble the women from observational studies indicate a consistency between the 2 types of study designs with similar benefit of HT on the reduction of CHD and overall mortality (Figure 1).

The “window of opportunity” for maximal expression of the beneficial effects of HT on CHD and overall mortality appears to be initiation of HT within 6 years of menopause and/or before 60 years of age and continued for 6 years or more.

Unlike lipid-lowering and aspirin therapy, HT reduces CHD and more importantly, overall mortality in this subgroup of women. Due to this reduced overall mortality, there is a substantial increase in QALYs in younger postmenopausal women who initiate HT in close proximity to menopause supporting HT as a highly-cost effective strategy for improving quality-adjusted life.

No other single preventive therapy offers systemic-wide effects for women and as such, the use of HT in the primary prevention of disease must be considered differently than medications currently used for prevention that are limited to a single organ system. Administration of exogenous estrogen during menopause should not be viewed as a therapy for any specific disease entity but as a replacement for a hormone that appears by the cumulated data to lessen the impact of aging on a multitude of organ systems such as the cardiovascular, skeletal and potentially the central nervous systems (Hodis and Mack, 2007a).

Timing in the initiation of hormone replacement before tissue damage due to aging becomes too extensive appears to be the key for successful prevention and amelioration of any further damage (Hodis and Mack, 2007a)

8A) Hodis, Howard N., and Wendy J. Mack. “Postmenopausal hormone therapy and cardiovascular disease in perspective.Clinical obstetrics and gynecology 51.3 (2008): 564-580.

The totality of data indicate that the window of opportunity for reducing mortality and coronary heart disease (CHD) is initiation of hormone therapy (HT) within 6 years of menopause and/or by 60 years of age and continued for 6 years or more. Additionally, the risks of HT are rare (<1/1,000) especially in younger postmenopausal women and comparable to other primary prevention therapies. In fact, as randomized controlled trial results accumulate, the more they look like the consistent observational data that young postmenopausal women with menopausal symptoms who use HT for long periods of time have lower rates of mortality and CHD than comparable postmenopausal women who do not use HT.

9) Hodis, Howard N., and Wendy J. Mack. “In perspective: estrogen therapy proves to safely and effectively reduce total mortality and coronary heart disease in recently postmenopausal women.” Menopause management 17.2 (2008): 27.

10) In Perspective: Estrogen Therapy Safely and Effectively Reduces Total Mortality and Coronary  Heart Disease in Recently Menopausal Women Howard N. Hodis, MD Wendy J. Mack, PhD
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Early Menopause

11) Lubiszewska, Barbara, et al. “The impact of early menopause on risk of coronary artery disease (PREmature Coronary Artery Disease In Women–PRECADIW case-control study).” European Journal of Preventive Cardiology 19.1 (2012): 95-101.

323 women (less than 55 years) with established CAD, enrolled between April 2005 and January 2008, and 347 age-matched healthy women .  Smoking, parental history of premature CVD, diabetes, menopause and hypertension were the strongest risk markers for premature CAD with ORs (95% CI): 3.83 (2.52–5.82); 3.08 (1.85–5.14); 2.89 (1.59–5.23); 2.82 (1.91–4.19); 2.39 (1.16–3.54).

Conclusions: We have shown that smoking and early postmenopausal stage (=3years) are the most important determinants of premature CAD followed by parental CVD, diabetes and hypertension.

Premature Ovarian Failure

12) Maclaran, Kate, Etienne Horner, and Nick Panay. “Premature ovarian failure: long-term sequelae.Menopause International 16.1 (2010): 38-41.

Life-expectancy: POF has been associated with a 50% higher mortality than women with menopause at age 52–55.12

A large prospective cohort study of 20,555 women demonstrated significantly increased all-cause mortality in those with menopause before 40 years after adjustment for confounding factors (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.15–1.71) and life-expectancy was reduced by two years compared with women with menopause between 50 and 54 years.13

The Mayo Clinic Cohort Study of Oophorectomy and Aging14 demonstrated that mortality was significantly higher in women who had received prophylactic bilateral oophorectomy before the age of 45 years (HR 1.67; 95% CI 1.16–2.40).

This increased mortality was however limited to those who did not receive estrogen replacement therapy up to the age of 45 years, therefore suggesting that estrogen may have a protective role.

Cardiovascular disease

An association between early menopause and increased mortality from cardiovascular disease has been established for many years,15 with an estimated 80% increase risk of mortality from ischaemic heart disease in those with menopause under the age of 40 compared with those with menopause at 49–55.12

This risk of ischaemic heart disease was more pronounced in those who had never used estrogens. It has also been demonstrated that cardiovascular mortality in women oophorectomized before the age of 45 and not receiving RT was significantly increased (HR 1.84; 95% CI 1.27–2.6) and that estrogen replacement may reduce this risk. The Danish Nurses cohort study showed that the risk of ischaemic heart disease was greater in POF if of surgical rather than spontaneous nature.16 Additionally, they demonstrated a benefit from estrogen replacement therapy in surgical patients, but not those with spontaneous POF.

Impaired ovarian function is thought to cause increased atherosclerosis progression based on non-human primate models17 and angiographic studies of estrogen deficiency of hypothalamic nature.18

Women with POF have been demonstrated to have impaired endothelial function which is often considered as a precursor to atherosclerosis.19

No long-term trials have assessed the primary prevention of cardiovascular disease in POF. As mentioned, a protective effect of estrogens has been demonstrated in observational studies, especially in surgically induced POF. Estrogen replacement has been shown to restore endothelial function in POF,19 but whether this results in reduced cardiovascular mortality remains unanswered.

Osteoporosis

The detrimental effects of declining estrogen levels on bone density in menopausal women have long been recognized. Women with POF have significantly lower bone density compared with controls.24,25 Both spontaneous and iatrogenic early menopause result in lower bone mineral density compared with controls and this is associated with a significantly higher overall fracture risk.26

The low bone density in POF can be mainly attributed to the period of accelerated bone loss, which occurs during the 4–5 years after the menopause with bone loss subsequently plateauing thereafter.

Estrogen replacement in those with early menopause does appear to reduce the risk of fracture if used for at least three years.27 Additionally, all patients should be encouraged to take regular weight-bearing exercise and have a calcium-rich diet, with consideration of calcium and vitamin D supplementation. There is currently no evidence for the use of non-hormonal treatments such as bisphosphonates, strontium or raloxifene in POF.

Cognitive function

It has been suggested that patients with early menopause may be at increased risk of dementia or reduced cognitive function. The Mayo Clinic Cohort Study of Oophorectomy and Aging has investigated the risk of cognitive impairment28 and parkinsonism29 in women undergoing premenopausal oophorectomy. They demonstrated that women who underwent either unilateral or bilateral oophorectomy before the onset of menopause had an increased risk of cognitive impairment or dementia compared with controls (HR = 1.46; 95% CI 1.13–1.90) and this risk increased with younger age at oophorectomy.

They also demonstrated a protective role for estrogen replacement in women with bilateral oophorectomy when taken until at least 50 years of age.28

A further study from the same group showed that unilateral or bilateral oophorectomy performed prior to menopause was associated with increased risk of parkinsonism and that the risk was increased at younger age of oophorectomy.29 Definitive conclusions regarding the risk of cognitive impairment in POF cannot yet be drawn due to a lack of data in women under the age of 40 and with non-surgical aetiologies.

Psychological effects

The diagnosis of POF can have a devastating effect psychologically and this aspect of management is often neglected. Unfortunately, the psychological effects can be long lasting and patients with POF have been shown to have increased anxiety, depression, somatization, hostility, sensitivity and psychological distress and decreased overall wellbeing, self-esteem and life satisfaction compared with control groups.30–32 They also have perceived lower levels of social support.33 Studies have shown high levels of psychological distress in both users and non-users of RT, highlighting the importance of psychological care within the management of these patients. Patients should be made aware of available support groups such as the Daisy Network (www.daisynetwork.org.uk) and Women’s Health Concern (www.womens-health-concern.org).

Sexual function

Women with POF have been shown to have decreased sexual wellbeing and are less satisfied with their sex lives suffering from reduced arousal, less frequent sexual encounters and increased pain.32 The age of diagnosis plays an important role with younger women more likely to develop complex psychosexual impairment.34 Management of sexual dysfunction should incorporate sexual counselling in addition to adequate estrogen replacement and consideration of androgen replacement.

Associated endocrine and autoimmune conditions

Patients with POF are at increased risk of other autoimmune disorders. At least 20% of patients with idiopathic POF will present with another autoimmune condition,35 most commonly hypothyroidism but also diabetes, Addisons disease, systemic lupus erythematosus, rheumatoid arthritis and myasthenia gravis. Patients should be tested for autoimmune antibodies, including antiadrenal antibodies as if present confer a 50% risk of developing adrenal insufficiency – a potentially fatal condition.36

Hysterectomy Surgical Menopause and Increased Heart Disease

12A) Parker, William H., et al. “Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study.” Obstetrics & Gynecology 113.5 (2009): 1027-1037.

12B) Rivera, Cathleen M., et al. “Increased cardiovascular mortality after early bilateral oophorectomy.Menopause 16.1 (2009): 15-23.

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Monkey Studies

13) Clarkson, Thomas B. “Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression.” Menopause 25.11 (2018): 1262-1274.

Both monkeys and women with premenopausal estrogen deficiency develop premature atherosclerosis, an effect that can be prevented in both species by estrogen-containing oral contraceptives.

PERIMENOPAUSAL/EARLY POSTMENOPAUSAL YEARS: During this stage, there are robust estrogen benefits. Monkeys given estrogens immediately after surgical menopause have a 70% inhibition in coronary atherosclerosis progression.

Estrogen treatment prevented progression of atherosclerosis of women in the Estrogen in the Prevention of Atherosclerosis Trial. A meta-analysis of women younger than 60 years given hormone therapy had reduced total mortality (relative risk = 0.61, 95% CI: 0.39-0.95).

Monkey Model

13A) Williams, J. Koudy, and Irma Suparto. “Hormone replacement therapy and cardiovascular disease: lessons from a monkey model of postmenopausal women.ILAR journal 45.2 (2004): 139-146.

Initiation of ERT with No Pre-existing Atherosclerosis

In two separate studies, Clarkson and colleagues (1998) and Adams and coworkers (1997) initiated ERT (CEE given in the diet at the monkey equivalent of 0.625 mg/day) immediately after ovariectomy in monkeys with no pre-existing atherosclerosis. In both of these studies (Figure 2), CEE inhibited the very early progression of atherosclerosis by about 70% compared with untreated controls.

Initiation of CEE with Pre-existing Atherosclerosis

In a more recent study, Clarkson and colleagues (2001) initiated CEE treatment immediately after ovariectomy in monkeys with pre-existing atherosclerosis. CEE inhibited further development of coronary artery atherosclerosis, but only by about 50% (compared with untreated controls, Figure 3). This treatment regimen would be equivalent to treating a postmenopausal woman with average amounts of pre-existing coronary artery atherosclerosis immediately after the onset of menopause.

This population is still different from the study populations used in the HERS, ERA (Estrogen/ Progestin Replacement and Atherosclerosis Trial; Herrington et al. 2000), and WHI trials, which did not receive RT until several years after the onset of menopause.

MONKEYS CEE reduced atheroclerosis by 72%, but not MPA

13B) Adams, Michael R., et al. “Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis.Arteriosclerosis, thrombosis, and vascular biology 17.1 (1997): 217-221.

Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis, the effects of combined (estrogen plus progestin) hormone-replacement therapy are uncertain. Some observational data indicate that users of combined hormone replacement consisting of continuously administered oral conjugated equine estrogens (CEE) and oral sequentially administered (7 to 14 days per month) medroxyprogesterone acetate (MPA) experience a reduction in risk similar to that of users of CEE alone.

However, the effects of combined, continuously administered CEE plus MPA (a prescribing pattern that has gained favor) on the risk of coronary heart disease or atherosclerosis are not known. We studied the effects of CEE (monkey equivalent of 0.625 mg/d) and MPA (monkey equivalent of 2.5 mg/d), administered separately or in combination, on the extent of coronary artery atherosclerosis (average plaque size) in surgically postmenopausal cynomolgus monkeys fed atherogenic diets and treated with these hormones for 30 months. Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% relative to untreated (estrogen-deficient) controls (P < .004)…Atherosclerosis extent in animals treated with CEE plus MPA or MPA alone did not differ from that of untreated controls.

Although the mechanism(s) remains unclear, we conclude that oral CEE inhibits the initiation and progression of coronary artery atherosclerosis and that continuously administered oral MPA antagonizes this atheroprotective effect.

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Transdermal Does Not Cause clots

14) Speroff, L. “Transdermal hormone therapy and the risk of stroke and venous thrombosis.Climacteric 13.5 (2010): 429-432.

Recent case-control and cohort studies have indicated that the transdermal administration of postmenopausal estrogen therapy is not associated with an increased risk of cardiovascular complications, specifically stroke and venous thrombosis. These studies have prompted the clinical promotion of transdermal treatment as ‘safer’. There are reasons, however, to be cautious regarding postmenopausal transdermal hormone therapy, especially in regard to stroke. Previous reports linking postmenopausal estrogen therapy and the risk of stroke have not yielded consistent results, finding it difficult to adjust for all confounding factors, including compliance with treatment. Age of the population studies may be a critical issue. Notably, the risk of stroke with oral estrogen was not increased in the Women’s Health Initiative when women with prior cardiovascular disease or those older than 60 years were excluded. There does appear to be a dose-response relationship with stroke, similar to that observed with estrogen-progestin contraceptives, and this may be a problem when studying standard doses of transdermal treatment, in that many women receiving transdermal estrogen display lower estrogen blood levels when compared with oral treatment. Clinicians should administer low doses of estrogen to women with risk factors for stroke, and the transdermal route of administration is indicated for women at high risk for venous thrombosis and for older postmenopausal women, especially for women with stroke risk factors. In a recent study, Renoux and colleagues from McGill University in Montreal performed a nested case-control study deriving the data from a cohort of women in the UK General Practice Research Database (GPRD).

Current use of oral and transdermal hormone therapy, based on recorded prescriptions, was compared to no use in 15 710 cases and 59 958 controls. The adjusted rate ratio (RR) for stroke for current use of transdermal estrogens, with or without a progestin, was not increased (RR 0.95; 95% confidence interval (CI) 0.75-1.20) compared with a significant increase associated with oral estrogen, with or without a progestin (RR 1.28; 95% CI 1.15-1.42). This would amount to an attributal risk of 0.8 additional strokes per 1000 women per year. There was an indication of a dose-response relationship; a significant increase in risk was observed with transdermal estrogen doses greater than 50 microg.

The case-control study by Renoux and colleagues is the first major analysis to compare transdermal and oral hormone therapy and conclude that, compared with an increased risk of stroke with oral therapy, there was no increased risk with transdermal treatment at a dose of 50 microg or less.

This report is about as strong an observational study as can be achieved.

Large numbers of cases (15 710) and controls (59 958) were available for analysis using the well-known UK GPRD. The use of this computerized database precludes selection bias by the investigators and recall bias by the women in the study. The results support the growing conventional wisdom that transdermal therapy at standard doses is free of the cardiovascular risks associated with oral therapy.
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15) LaCroix, Andrea Z., et al. “Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial.Jama 305.13 (2011): 1305-1314.

Context The Women’s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.

Objective To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009.

Design, Setting, and Participants The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10 739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent.

Main Outcome Measures The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.

Results The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95).

Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).

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11 year follow up of the WHI

16) Anderson, Garnet L., et al. “Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial.The lancet oncology 13.5 (2012): 476-486.

By contrast with many observational studies, women in the Women’s Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort.

METHODS:Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US clinical centres into a randomized, double-masked, placebo-controlled trial. Women aged 50-79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611.

FINDINGS:

After a median follow-up of 11·8 years (IQR 9·1-12·9), the use of oestrogen for a median of 5·9 years (2·5-7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62-0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61-1·02) and post-intervention phase effects (0·75, 0·51-1·09). In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13-0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39-0·97; p=0·04).

INTERPRETATION:

Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer.

17) Rossouw, Jacques E., et al. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial.” Jama 288.3 (2002): 321-333.

Coronary Calcium Studies

JoAnn Manson

18) Manson, JoAnn E., et al. “Estrogen therapy and coronary-artery calcification.New England Journal of Medicine 356.25 (2007): 2591-2602.

The WHI-CACS assessed the post-trial burden of calcified atheroma in the coronary arteries in women 50 to 59 years old at the time of randomization in the WHI trial of conjugated equine estrogens. An average of 8.7 years after randomization, women receiving estrogen had a lower prevalence and quantity of coronary-artery calcium than those receiving placebo, with odds ratios for high levels of coronary-artery calcium generally 30 to 40% lower in intention-to-treat analyses and 60% lower in analyses among women with at least 80% adherence to the study medication for at least 5 years. The results remained robust and significant in analyses that involved diverse analytic approaches. These findings, in conjunction with the suggestion of a reduced risk of clinical coronary events among women treated with conjugated equine estrogens in this age group,5 are consistent with previous evidence from laboratory, animal, and observational studies.2,3,6

Matthew Budoff –

19) Budoff, Matthew J., et al. “Effects of hormone replacement on progression of coronary calcium as measured by electron beam tomography.” Journal of women’s health 14.5 (2005): 410-417.

The recent Women’s Health Initiative (WHI) results have demonstrated that combined estrogen plus progestin imparts a small but significant increase in cardiovascular risk and breast cancer among asymptomatic women. However, the effect and potential benefit of unopposed estrogen is not as clear. We sought to evaluate the progression of subclinical atherosclerosis in postmenopausal women using no hormone replacement therapy (RT), combined therapy, and estrogen alone in an observational study.
METHODS:

Postmenopausal women without symptoms or known coronary heart disease (CHD) were evaluated at our center for follow-up of coronary calcification. Patients were physician referred and underwent two consecutive electron beam tomography scans at least 1 year apart. All women fitting the study criteria were asked to participate, and those who consented were included. Demographic data, risk factors for CHD, RT, and other medication use were collected by interview.
RESULTS:

The study included 177 asymptomatic women.

Calcium progression was 14.6%+/-21% in women taking any hormone therapy (n=97). Annual calcium progression rates in nonusers (n=80) was 22.3%+/-32%.

Relative to the nonuser group, RT treatment inhibited the progression of atherosclerosis by 35% (p=0.01). This effect was independent of age, risk, cardiovascular factors, statin use, or baseline CAC score.

Thirty-five of the 97 women (36%) were taking estrogen plus progestin, with an annual increase in calcium scores of 24%+/-23%, similar to the non-RT women (22%).

Those women taking estrogen replacement only (n=62) was 63% lower (9%+/-22%).

CONCLUSIONS:

This is an observational study, and the results are in accordance with the recently published WHI study, demonstrating no benefit of estrogen plus progestin compared with no therapy. However, women taking unopposed estrogen demonstrated a significant slowing of subclinical atherosclerosis compared with non-RT and estrogen plus progestin.

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Mechanisms- Endothelial Dysfunction

20) http://www.hellenicjcardiol.org/archive/full_text/2009/4/2009_4_303.pdf

Bechlioulis, Aris, et al. “Menopause and hormone therapy: from vascular endothelial function to cardiovascular disease.Hellenic J Cardiol 50.4 (2009): 303-15.

23 RCT’s Show Benefit for Younger post menopause

21) Salpeter, Shelley R., et al. “Brief report: coronary heart disease events associated with hormone therapy in younger and older women: a meta-analysis.Journal of general internal medicine 21 (2006): 363-366.

RESULTS -The literature search identified 23 trials that met inclusion criteria (Appendices 1 and 2).2,3,8–29 Additional information on the WHI trial was published separately.30

The analysis included 39,049 participants, with a mean trial duration of 4.9±1.7 years (range 0.5 to 10 years). The dropout rate was approximately 12.0% in the treatment group and 10.8% in the control group.

For all ages, there was no effect of HT on CHD events (OR 0.99 [confidence interval (CI), 0.88 to 1.11]).

In the younger group, HT reduced CHD events by 32% (OR 0.68 [CI, 0.48 to 0.96; Fig. 1]). When trials with only younger women were evaluated, a similar reduction in events was found (OR 0.7 [CI, 0.49 to 1.0]).

The OR for CHD events in the older group was 1.03 (CI, 0.91 to 1.16; Fig. 2). Trials with only older women showed similar results (OR 1.08 [CI, 0.91 to 1.27]). When the results of the 2 age groups were compared with each other, HT was associated with significantly lower CHD events in younger women compared with older women (OR 0.66 [CI, 0.46 to 0.95]).

HERS-Study failure to show benefit because they used Prem-Pro and average age was 67 yrs.

22) Grady, Deborah, et al. “Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II).Jama 288.1 (2002): 49-57.

The Heart and Estrogen/progestin Replacement Study (HERS) found no overall reduction in risk of coronary heart disease (CHD) events among postmenopausal women with CHD. However, in the hormone group, findings did suggest a higher risk of CHD events during the first year, and a decreased risk during years 3 to 5.

Randomized, blinded, placebo-controlled trial of 4.1 years’ duration (HERS) and subsequent unblinded follow-up for 2.7 years (HERS II) conducted at outpatient and community settings at 20 US clinical centers.
PARTICIPANTS:

A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II.

Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate (n = 1380), or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians’ discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group, and increased from 0% (year 1) to 8% (year 6) in the placebo group.

MAIN OUTCOME MEASURES:

The primary outcome was nonfatal myocardial infarction and CHD death. Secondary cardiovascular events were coronary revascularization, hospitalization for unstable angina or congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient ischemic attack, and peripheral arterial disease.

RESULTS:

There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS, HERS II, or overall. The unadjusted relative hazard (RH) for CHD events in HERS was 0.99 (95% confidence interval [CI], 0.81-1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19).

CONCLUSIONS:

Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.

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Mechanism of Protection – Estrogen

23) Miller, Virginia M., and Sue P. Duckles. “Vascular actions of estrogens: functional implications.Pharmacological reviews 60.2 (2008): 210-241.

Effect of estrogen on neointima formation

24) Xing, Dongqi, et al. “Estrogen and mechanisms of vascular protection.” Arteriosclerosis, thrombosis, and vascular biology 29.3 (2009): 289-295.

Estrogen exerts an early antiinflammatory effect in the rat carotid injury model.4,13,18 This is reflected in an estrogen dependent sexual dimorphism in the vascular injury response, whereby neointima formation (influx of adventitial and medial cells and deposition of interstitial matrix inside the internal elastic lamella) is greater in males than in females.5,6,8,17,38 Further, treatment with a dose of estrogen that results in physiological levels (40 to 60 pg/mL) of circulating hormone markedly attenuates neointima formation in gonadectomized animals of both sexes. Interestingly, coadministration of medroxyprogesterone acetate (MPA), the synthetic progestin contained in many menopausal hormone preparations and studied in the Women’s Health Initiative, completely blocks the effect of estrogen on neointima formation.8

25) Yang, Xiao-Ping, and Jane F. Reckelhoff. “Estrogen, hormonal replacement therapy and cardiovascular disease.” Current opinion in nephrology and hypertension 20.2 (2011): 133-138.

There is evidence that atherosclerosis involves an ongoing inflammatory response, which is more profound during the early years of menopause [,,]. Cytokine production has been shown to increase in the early years following menopause but thereafter declines to within the premenopausal range [,]. Estrogen reportedly reduces interleukin (IL)-1, IL-6, IL-18, C-reactive protein, tissue necrosis factor (TNF)-α and increases macrophage colony-stimulating factor, a cytokine that lowers plasma cholesterol levels by enhancing clearance of low-density lipoprotein [,]. Thus since inflammatory responses are higher in early postmenopause while absence or reduction of endogenous estrogen may accelerate the progression of atherosclerosis, the timing of HRT with respect to onset of menopause may have important ramifications regarding its efficacy in preventing or delaying the progression of atherosclerosis and CVD

Anti-inflammatory Effect of Estrogen

26) Xing, Dongqi, et al. “Estrogen and mechanisms of vascular protection.” Arteriosclerosis, thrombosis, and vascular biology 29.3 (2009): 289-295.

we review cellular/molecular mechanisms by which estrogen modulates injury-induced inflammation, growth factor expression, and oxidative stress in arteries and isolated vascular smooth muscle cells, with emphasis on the role of estrogen receptors and the nuclear factor-κB (NFκBeta signaling pathway, as well as evidence that these protective mechanisms are lost in aging subjects.

27) Miller, Andrew P., et al. “Hormone replacement therapy and inflammation: interactions in cardiovascular disease.” Hypertension 42.4 (2003): 657-663.  Hormone replacement therapy and inflammation in cardiovascular disease Miller Andrew Hypertension 2003

Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Atherogenesis begins with endothelial damage, and the damaged endothelium expresses adhesion molecules, chemokines, and proinflammatory cytokines that direct atherosclerotic plaque formation and spill into the circulation as biomarkers of atherosclerotic disease risk.

Menopausal hormone therapy, including a variety of estrogen preparations with or without a progestin, has negative modulatory effects on most of these soluble inflammatory markers, including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-α, inconsistent effects on interleukin-6, and stimulatory effects on transforming growth factor-β, a vasoprotective cytokine. In contrast, C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen.The finding that transdermal estradiol, unlike oral conjugated estrogen, does not elevate circulating CRP levels

As surrogate markers of vascular inflammation, plasma levels of a variety of adhesion molecules, cytokines, and acute phase reactants have been studied and validated as predictors of future cardiovascular events in both women and men. In prospective studies, administration of ovarian hormones to postmenopausal women has been shown to negatively modulate most of these soluble markers, with significant decreases in E-selectin, sVCAM1, sICAM-1, and TNF-α. In contrast, oral hormone therapy increases CRP.

28) Mendelsohn, Michael E. “Protective effects of estrogen on the cardiovascular system.The American journal of cardiology 89.12 (2002): 12-17.

Estrogen upregulates EPC’s

29) Hamada, Hiromichi, et al. “Estrogen receptors α and β mediate contribution of bone marrow–derived endothelial progenitor cells to functional recovery after myocardial infarction.” Circulation 114.21 (2006): 2261-2270.

Background— Estradiol (E2) modulates the kinetics of circulating endothelial progenitor cells (EPCs) and favorably affects neovascularization after ischemic injury. However, the roles of estrogen receptors α (ERα) and β (ERβ) in EPC biology are largely unknown.

Methods and Results— In response to E2, migration, tube formation, adhesion, and estrogen-responsive element–dependent gene transcription activities were severely impaired in EPCs obtained from ERα-knockout mice (ERαKO) and moderately impaired in ERβKO EPCs. The number of ERαΚΟ EPCs (42.4±1.5; P<0.001) and ERβKO EPCs (55.4±1.8; P=0.03) incorporated into the ischemic border zone was reduced as compared with wild-type (WT) EPCs (72.5±1.3). In bone marrow transplantation (BMT) models, the number of mobilized endogenous EPCs in E2-treated mice was significantly reduced in ERαKO BMT (WT mice transplanted with ERαKO bone marrow) (2.03±0.18%; P=0.004 versus WT BMT) and ERβKO BMT (2.62±0.07%; P=0.02 versus WT) compared with WT BMT (2.87±0.13%) (WT to WT BMT as control) mice. Capillary density at the border zone of ischemic myocardium also was significantly reduced in ERαKO BMT and ERβKO BMT compared with WT mice (WT BMT, 1718±75/mm2; ERαKO BMT, 1107±48/mm2; ERβKO BMT, 1567±50/mm2). ERα mRNA was expressed more abundantly on EPCs compared with ERβ. Moreover, vascular endothelial growth factor was significantly downregulated on ERαKO EPCs compared with WT EPCs both in vitro and in vivo.

Conclusions— Both ERα and ERβ contribute to E2-mediated EPC activation and tissue incorporation and to preservation of cardiac function after myocardial infarction. ERα plays a more prominent role in this process. Moreover, ERα contributes to upregulation of vascular endothelial growth factor, revealing possible mechanisms of an effect of E2 on EPC biology. Finally, these data provide additional evidence of the importance of bone marrow–derived EPC phenotype in ischemic tissue repair.

Histology Study of Carotid Plaque in Hormone Users

30) Marfella, Raffaele, et al. “Proteasome Activity as a Target of Hormone Replacement Therapy–Dependent Plaque Stabilization in Postmenopausal Women.Hypertension 51.4 (2008): 1135-1141.

Now, in the present report, we provide evidence for the critical involvement of UPS in the process of plaque stabilization realized by RT in postmenopausal women. In particular, we evidence an inhibitory effect of RT on UPS activity in human atherosclerotic lesions, show in humans the possibility of UPS activity regulation in an oxidative stress-dependent fashion, and finally we associate the inhibition of UPS with the reduction of inflammation during RT. Lower expression and activity of UPS was found in specimens obtained from carotid lesions of postmenopausal women treated with RT compared with specimens obtained from women never treated with RT.

Perspectives

This study proposes an interesting hypothesis for addressing the missing link between RT and plaque stabilization in postmenopausal women by demonstrating the inhibition of the functional UPS/oxidative stress axis in human atherosclerotic lesions and by providing evidence that it is associated with plaque stabilization possibly by suppression of the NF-KappaBeta–induced inflammation promoting plaque rupture. However, it is worth noticing that, for statins and antagonists of the rennin-angiotensin system, 2 of the most successful drugs in cardiovascular diseases, an antioxidative and a proteasome inhibitory effect have been described.32,33 Whether this is an effect that relates to their clinical benefit, however, awaits further investigation. These findings are also potentially important from a practical standpoint, because they raise the interesting possibility that modification of the UPS activity by RT might provide a novel form of therapy for plaque stabilization of elderly women with atherosclerotic disease and prevention of acute ischemic syndromes.

30B) Versari, Daniele, et al. “Dysregulation of the ubiquitin-proteasome system in human carotid atherosclerosis.” Arteriosclerosis, thrombosis, and vascular biology 26.9 (2006): 2132-2139.

Animal Models- genetically manipulated mice

31) Nofer, Jerzy-Roch. “Estrogens and atherosclerosis: insights from animal models and cell systems.Journal of molecular endocrinology 48.2 (2012): R13-R29.

Studies on animal models of atherosclerosis provided compelling evidence that physiological estrogen levels potently attenuate both early and advanced stages of atherosclerosis lesion development in females and suggested similar protective effects in males.

Estradiol metabolite in genetically manipulated mice is protective

32) Bourghardt, Johan, et al. “The endogenous estradiol metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient mice.” Endocrinology 148.9 (2007): 4128-4132.

Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice.

Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17beta-estradiol (6 microg/d), or 2-methoxyestradiol [6.66 microg/d (low-dose) or 66.6 microg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group.

En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%).

In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens.

Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

Estrogen Deficiency causes Cognitive Impaiment

33) Rocca, W. A., et al. “Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.” Neurology 69.11 (2007): 1074-1083.

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Estrogen Deficiency Causes Auto-Immune Disease

9% of POV had anti-adrenal antibodies

34) http://jcem.endojournals.org/content/82/3/932

Betterle, Corrado, et al. “Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison’s disease.The Journal of Clinical Endocrinology & Metabolism 82.3 (1997): 932-938.
Adrenal cortex antibodies (ACA) were measured by immunofluorescence in 8840 adult patients with organ-specific autoimmune diseases without overt hypoadrenalism. Sixty-seven (0.8%) patients were ACA-positive, with the highest prevalence in those with premature ovarian failure (8.9%). Forty-eight ACA-positive and 20 ACA-negative individuals were enrolled into a prospective study. Antibodies to steroid 21-hydroxylase (21-OH), steroid 17a-hydroxylase (17a-OH) and cytochrome P450 side chain cleavage enzyme (P450scc) were measured by immunoprecipitation assay. Human leucocyte antigens D-related (HLA-DR) genotyping was also carried out and adrenal function assessed by ACTH test. On enrollment, 75% of ACA-positive patients had a normal adrenal function, while 25% revealed a subclinical hypoadrenalism. 21-OH antibodies were positive in 91% of ACA-positive sera. Eleven patients were positive for steroid-cell antibodies by immunofluorescence, and 9 revealed a positivity for antibodies to 17a-OH and/or P450scc. During the prospective study, overt Addison’s disease developed in 21% and subclinical hypoadrenalism in 29% of ACA-positive patients, while 50% maintained normal adrenal function. Progression to Addison’s disease was more frequent in patients with subclinical hypoadrenalism, high titers of ACA and higher levels of 21-OH antibodies, complement-fixing ACA and HLA-DR3 status. All 20 persistently ACA-negative patients were also negative for antibodies to 21-OH, 17a-OH, and P450scc, and all maintained normal adrenal function during follow-up. In conclusion, the detection of ACA/21-OH antibodies in adults is a marker of low progression toward clinical Addison’s disease.

Hormones Improve Bone Density by 5% over 3.5 yrs.

35) Recker, Robert R., et al. “The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women: a randomized, controlled trial.” Annals of internal medicine 130.11 (1999): 897-904.

Background: Hormone replacement therapy (RT), the mainstay of osteoporosis prevention, is limited because of dose-related risks, side effects, and patient acceptance. The bone-sparing efficacy and tolerability of the lowest available doses of RT have not been adequately studied in elderly women.

Objective: To determine the bone-sparing effect of continuous low-dose RT in elderly women.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: University osteoporosis research and clinical center.

Patients: 128 healthy white women (age > 65 years) with low bone mass recruited by word of mouth and by local advertisement. The principal eligibility criterion was spinal bone mineral density of 0.90 g/cm2 or less.

Intervention: Continuous therapy with conjugated equine estrogen, 0.3 mg/d, and medroxyprogesterone, 2.5 mg/d, or matching placebo. Sufficient calcium supplementation was given to bring all calcium intakes above 1000 mg/d in both groups; supplemental oral 25-hydroxyvitamin D was given to maintain serum 25-hydroxyvitamin D levels of at least 75 nmol/L in both groups.

Measurements: Bone mineral density of the spine, hip, total body, and forearm; serum total alkaline phosphatase and serum osteocalcin levels at 6-month intervals; and 24-hour urine creatinine and hydroxyproline excretion at baseline, 12 months, and 42 months.

Results: During 3.5 years of observation, spinal bone mineral density increased by 3.5% (P < 0.001) in an intention-to-treat analysis and by 5.2% among patients with greater than 90% adherence to therapy. Significant increases were seen in total-body and forearm bone density (P < 0.01). Symptoms related to RT (breast tenderness, spotting, pelvic discomfort, and mood changes) were mild and short-lived.

Conclusions: Continuous low-dose RT with conjugated equine estrogen and oral medroxyprogesterone combined with adequate calcium and vitamin D provides a bone-sparing effect that is similar or superior to that provided by other, higher-dose RT regimens in elderly women. This combination is well tolerated by most patients.
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Adrenal Antibody Screen with Reflex to Titer

Service code 4645  CPT Code(s): 86255,86256  Includes: If  Adrenal Antibody Screen is positive, Adrenal Antibody Titer with Pattern will be performed at an additional charge (CPT code(s): 86256).

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HEART DISEASE- Danish Nurse Cohort Study

36) Løkkegaard, E., et al. “The association between early menopause and risk of ischaemic heart disease: influence of hormone therapy.Maturitas 53.2 (2006): 226-233.

Abstract

Randomised clinical trials find no protection against development of ischaemic heart disease by use of Hormone Therapy (HT) after the age of 50 years. Observational studies suggest that early menopause is a risk factor for ischaemic heart disease. Yet, a clinical very relevant question is whether HT reduces this risk associated with early menopause.

OBJECTIVE:

To analyse whether early menopause based on various causes are independent risk factors for ischaemic heart disease, and to investigate whether the risks are modified by use of HT.

METHODS:

In a prospective cohort study questionnaires were mailed to Danish female nurses above 44 years of age in 1993. Information on menopause, use of HT and lifestyle was obtained. In total 19,898 (86%) nurses fulfilled the questionnaire, among them 10.533 were postmenopausal with definable menopausal age, free of previous ischaemic heart disease, stroke or cancer. Through individual linkage to national register incident cases of ischaemic heart disease were identified until end of 1998.

RESULTS:

Menopause below both age 40 and 45 was associated with an increased risk of ischaemic heart disease, seeming most pronounced for women who had an early ovariectomy but also among spontaneous menopausal women. Generally HT did not reduce the risk except for the early-ovariectomised women, where no increased risk of ischaemic heart disease for HT users was found.

CONCLUSION:

We found an increased risk of ischaemic heart disease associated with early removal of the ovaries that might be reduced with HT. The present study need confirmation from other studies but suggests that early ovariectomised women could benefit from HT.

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37) Howell, Anthony, and Jack Cuzick. “Oestrogen and breast cancer: results from the WHI trial.” The Lancet Oncology 13.5 (2012): 437-438.

In The Lancet Oncology, the Women’s Health Initiative (WHI) investigators report1 that receipt of conjugated equine oestrogen for a median of 5·9 years reduced the risk of invasive breast cancer by 23% compared with placebo (151 cases in 5310 women who received oestrogen vs 199 cases in 5429 controls; p=0·02).

Women who did develop breast cancer after receipt of oestrogen had significantly reduced breast cancer-specific mortality (six deaths in the oestrogen group vs 16 deaths in controls; p=0·03) and all-cause mortality (30 deaths vs 50 deaths; p=0·04).

This preventive effect occurred at all ages and continued beyond the period of oestrogen use, a carryover effect also noted in prevention trials of tamoxifen.2

Although modest, the WHI results are significant and raise important questions about their disparity with many observational studies and the mechanism of reported benefit with oestrogen therapy.

Most observational studies on the use of oestrogen-only hormone replacement suggest an increased risk of breast cancer, whereas some show risk neutrality, and a few agree with the reduced risk reported by the WHI.3

Traditionally, randomized controlled trials have greater validity than do observational studies. However, the overall weight of evidence in terms of number of independent studies is also important, and the WHI trial is the only randomized controlled trial examining oestrogen therapy that supports this view.

The present results of WHI1 should be seen in the context of the update of the study in 2011 reporting the effects of oestrogen on overall health.8 No overall difference was noted in participants’ global index of health (including cardiovascular disease, thrombosis and embolism, breast and colorectal cancer, hip fracture, and death from all causes).

However this null result masks an unexpected but significant interaction with age (p=0·009) with health improvements in young women and health decrements in older women.

Young women (50—59 years) taking oestrogen were significantly less likely to have coronary heart disease, myocardial infarction, and death from all causes, not only with respect to older women but also placebo controls of the same age. The reasons for such an interaction with age deserve further investigation.

Whether the benefits of oestrogen therapy in young women can be translated to all oestrogen-only hormone replacement therapy is unknown, and perhaps only conjugated equine oestrogens should be prescribed at present.

The WHI investigators should be congratulated for providing insight into the value of conjugated equine oestrogens and young women can be reassured of the low risks and potentially striking benefits, provided that they are counselled about the small increases in thromboembolic disease as noted with most hormonal preparations.

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Statin Drugs for Primary Prevention in Women – NO reduction in Mortality

38) Walsh, Judith ME, and Michael Pignone. “Drug treatment of hyperlipidemia in women.Jama 291.18 (2004): 2243-2252.

39) Petretta, Mario, et al. “Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis.International journal of cardiology 138.1 (2010): 25-31.

We performed a meta-analysis including 8 randomized controlled trials (19,052 and 30,194 men, mean follow-up 3.9 years) that assessed the cardiovascular outcomes related to statin therapy, including studies that provided sex-specific results. MEDLINE and the Cochrane Database, were searched for articles published in English and other languages up to March 2008.

Statins do not appear to have a beneficial effect on total mortality for both men and women in primary prevention over the 2.8- to 5.3 year study period (men: 95% Confidence Interval (CI) 0.83-1.04; comparison p = 0.22; women: 0.96; CI 0.81-1.13; p = 0.61).

Statin therapy reduced the risk of coronary heart disease (CHD) events in men (0.59; CI 0.48-0.74; p = 0.0001), however in women this risk reduction was weakly significant (0.89 CI 0.79-1.00; p = 0.05) and disappeared when in sensitivity analysis, trials not entirely of primary prevention were excluded (HPS, PROSPER) (0.95 CI 0.78-1.16; comparison p = 0.562).

CONCLUSIONS:  Our study showed that statin therapy reduced the risk of CHD events in men without prior cardiovascular disease, but not in women. Statins did not reduce the risk of total mortality both in men and women.

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Kausik K. Ray- Archives – Statins and All Cause Mortality

40) Ray, Kausik K., et al. “Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65 229 participants.Archives of internal medicine 170.12 (2010): 1024-1031.

41) Dr. Sangeeta Pati Interview on the Wellness Hour with Randy Alvarez Jun 12, 2007 https://www.youtube.com/watch?v=hxOvbBI-FRQ

42) Raggi, Paolo, Tracy Q. Callister, and Leslee J. Shaw. “Progression of coronary artery calcium and risk of first myocardial infarction in patients receiving cholesterol-lowering therapy.” Arteriosclerosis, thrombosis, and vascular biology 24.7 (2004): 1272-1277.

43) Becker, Alexander, et al. “Comparison of progression of coronary calcium in postmenopausal women on versus not on estrogen/progestin therapy.” The American journal of cardiology 99.3 (2007): 374-378.

44) Khosla, Sundeep, et al. “The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed?.” Journal of bone and mineral research 26.3 (2011): 441-451.

45) Rocca, W. A., et al. “Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.” Neurology 69.11 (2007): 1074-1083.

46) Rapp, Peter R., John H. Morrison, and Jeffrey A. Roberts. “Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys.” Journal of neuroscience 23.13 (2003): 5708-5714.

47) Ali, Noor, et al. “The role of estrogen therapy as a protective factor for Alzheimer’s disease and dementia in postmenopausal women: A comprehensive review of the literature.” Cureus 15.8 (2023).

48) Gilmer, G., et al. “Uncovering the “riddle of femininity” in osteoarthritis: a systematic review and meta-analysis of menopausal animal models and mathematical modeling of estrogen treatment.” Osteoarthritis and cartilage 31.4 (2023): 447-457.

49) Gersh, Felice, et al. “Estrogen and cardiovascular disease.” Progress in Cardiovascular Diseases (2024).

50) Yang, Xiaohui, et al. “Meta-Analysis of Estrogen in Osteoarthritis: Clinical Status and Protective Effects.” Alternative therapies in health and medicine 29.1 (2023): 224-230.

51) Ruan, Xiangyan, and Alfred O. Mueck. “The choice of progestogen for HRT in menopausal women: breast cancer risk is a major issue.” Hormone Molecular Biology and Clinical Investigation 37.1 (2019): 20180019.

52) Bernstein, Paula, and Gerald Pohost. “Progesterone, progestins, and the heart.” Reviews in cardiovascular medicine 11.3 (2010): e141-9.

>53) Booth, Erin A., and Benedict R. Lucchesi. “Medroxyprogesterone acetate prevents the cardioprotective and anti-inflammatory effects of 17β-estradiol in an in vivo model of myocardial ischemia and reperfusion.” American Journal of Physiology-Heart and Circulatory Physiology 293.3 (2007): H1408-H1415.

54) Jeanes, Helen L., et al. “Medroxyprogesterone acetate inhibits the cardioprotective effect of estrogen in experimental ischemia-reperfusion injury.” Menopause 13.1 (2006): 80-86.

55) Adams, Michael R., et al. “Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis.” Arteriosclerosis, thrombosis, and vascular biology 17.1 (1997): 217-221.

Nurses Health Study

56) Grodstein, Francine, et al. “A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease.Annals of internal medicine 133.12 (2000): 933-941.

Background: Most primary prevention studies have found that long-term users of postmenopausal hormone therapy are at lower risk for coronary events, but numerous questions remain. An adverse influence of hormone therapy on cardiovascular risk has been suggested during the initial year of use; however, few data are available on short-term hormone therapy. In addition, the cardiovascular effects of daily doses of oral conjugated estrogen lower than 0.625 mg are unknown, and few studies have examined estrogen plus progestin in this regard.

Objective: To investigate duration, dose, and type of postmenopausal hormone therapy and primary prevention of cardiovascular disease.

Design: Prospective, observational cohort study.

Setting: Nurses’ Health Study, with follow-up from 1976 to 1996.

Patients: 70 533 postmenopausal women, in whom 1258 major coronary events (nonfatal myocardial infarction or fatal coronary disease) and 767 strokes were identified.
Measurements: Details of postmenopausal hormone use were ascertained by using biennial questionnaires. Cardiovascular disease was established by using a questionnaire and was confirmed by medical record review. Logistic regression models were used to calculate relative risks and 95% CIs, adjusted for confounders.

Results: When all cardiovascular risk factors were considered, the risk for major coronary events was lower among current users of hormone therapy, including short-term users, compared with never-users (relative risk, 0.61 [95% CI, 0.52 to 0.71]).

Conclusions: Postmenopausal hormone use appears to decrease risk for major coronary events in women without previous heart disease. Furthermore, 0.3 mg of oral conjugated estrogen daily is associated with a reduction similar to that seen with the standard dose of 0.625 mg. However, estrogen at daily doses of 0.625 mg or greater and in combination with progestin may increase risk for stroke.

www.ncbi.nlm.nih.gov/pmc/articles/PMC2637768/

57) Miller, Virginia M., and Sue P. Duckles. “Vascular actions of estrogens: functional implications.” Pharmacological reviews 60.2 (2008): 210-241.

Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered.

french cohort study 2008

58) Fournier, Agnès, Franco Berrino, and Françoise Clavel-Chapelon. “Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.” Breast cancer research and treatment 107 (2008): 103-111.

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 RT 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 RT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone.

================

59) Jordan, V. Craig, and Leslie G. Ford. “Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis.Cancer prevention research 4.5 (2011): 633-637.

Administration of estrogen replacement therapy (ERT) decreases the incidence of breast cancer, as shown in a double-blind, placebo-controlled randomized trial of the Women’s Health Initiative (WHI) in 10,739 postmenopausal women with a prior hysterectomy. Although paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances. Long-term antiestrogen treatment or estrogen deprivation causes the eventual development and evolution of antihormone resistance. Cell populations emerge with a vulnerability, as estrogen is no longer a survival signal but is an apoptotic trigger. The antitumor effect of ERT in estrogen-deprived postmenopausal women is consistent with laboratory models. Cancer Prev Res; 4(5); 633–7. ©2011 AACR.

As the WHI study of ERT shows (7), physiologic estrogen has delivered what the scientific database would now predict.

When the WHI was initiated in 1993, their present clinical result of a reduction in breast cancer was unanticipated (7) but is consistent nevertheless with parallel laboratory studies completed over the past 20 years.

Cumulative evidence to support low dose estrogen-induced apoptosis in long-term estrogen-deprived nascent breast cancer

Historical use of estrogens to treat breast cancer.
Physiologic estrogen as an antitumor agent in SERM-resistant breast cancer models in vivo.    Estrogen-induced apoptosis in estrogen-deprived ER-positive cell lines in vitro.
A current evaluation of estrogen to treat acquired antihormone resistance in metastatic breast cancer.
The extrapolation of the concept that physiologic estrogen kills breast cancer cells to adjuvant antihormone therapy.

Physiologic estradiol does not promote tumor growth, but small tumors undergo rapid and complete regression

60) Brünner, N., et al. “Effect of 17 β-oestradiol on growth curves and flow cytometric DNA distribution of two human breast carcinomas grown in nude mice.” British Journal of Cancer 47.5 (1983): 641-647.

The effect of 17 beta-oestradiol on a “receptor positive” and on a “receptor negative” human breast carcinoma grown in nude mice was studied. Experimental growth data were used to determine the effect on tumour growth. Flow cytometric DNA analysis (FCM) performed on tumour tissue obtained by sequential fine-needle aspirations was used to estimate the effect on the cell cycle. In the receptor-positive breast carcinoma, oestradiol induced complete tumour regression and characteristic cell cycle changes. In the receptor-negative breast carcinoma, no changes in tumour growth and cell cycle distribution could be demonstrated following the treatment. The results indicate that the oestradiol-induced cell kill could be explained to some extent by the induction of polyploid cells, which eventually die. Since the cell cycle changes monitored by FCM in the receptor-positive breast carcinoma appeared prior to any reduction in the tumour size, the results suggest that FCM may prove a valuable method in the early detection of tumour response to hormone treatment in human breast cancer.

61) LaCroix, Andrea Z., et al. “Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial.” Jama 305.13 (2011): 1305-1314.

Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95).

62) Jungheim, Emily S., and Graham A. Colditz. “Short-term use of unopposed estrogen: a balance of inferred risks and benefits.” Jama 305.13 (2011): 1354-1355.

Idiotic statement –  previously quoted studies used progestins.

“the reduced incidence of breast cancer persisted. This finding is inconsistent with a longstanding, corroborated body of evidence7,8? and raises the possibility that other important factors modify documented risks and benefits of estrogen therapy among these long-term WHI participants. ”

63) Anderson, Garnet L., et al. “Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial.The lancet oncology 13.5 (2012): 476-486.

Methods
Between 1993 and 1998, the WHI enrolled 10 739 postmenopausal women from 40 US clinical centres into a randomized, double-masked, placebo-controlled trial. Women aged 50—79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population.

Findings      After a median follow-up of 11·8 years (IQR 9·1—12·9), the use of oestrogen for a median of 5·9 years (2·5—7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62—0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61—1·02) and post-intervention phase effects (0·75, 0·51—1·09). In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13—0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39—0·97; p=0·04).
Interpretation
Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer.

http://www.lancet.com/journals/lanonc/article/PIIS1470-2045(12)70110-9/fulltext?_eventId=login

64) The Lancet Oncology, Early Online Publication, 7 March 2012 Oestrogen and breast cancer: results from the WHI trial  Anthony Howell Jack Cuzick

Young women (50—59 years) taking oestrogen were significantly less likely to have coronary heart disease, myocardial infarction, and death from all causes, not only with respect to older women but also placebo controls of the same age.

Observational and WHI studies agree on the increased risk of breast cancer with combined hormone replacement therapy (including a progestin).

“The WHI investigators should be congratulated for providing insight into the value of conjugated equine oestrogens and young women can be reassured of the low risks and potentially striking benefits,”

—————————————

http://www.latimes.com/health/la-he-estrogen-breast-cancer-20120307,0,1238385.story

65) Estrogen taken alone is linked to lower breast cancer risk  By Shari Roan, Los Angeles Times  March 7, 2012

An analysis finds that women who took the hormone by itself after menopause had a reduced risk of developing breast cancer. ”’

Dr. Rowan T. Chlebowski, an investigator at the Los Angeles Biomedical Research Institute in Torrance and chief of medical oncology and hematology at Harbor-UCLA Medical Center.said :  ” Estrogen alone for the period we studied seems to be pretty safe and maybe even beneficial.”

Researchers followed 7,645 women from the original group of almost 11,000 participants for almost five years to see what happened to them after stopping estrogen therapy. The study found that women who took estrogen had a 23% reduced risk of breast cancer compared with those who took a placebo.

Among the women who did develop breast cancer, those who took estrogen had a 63% reduced risk of dying from the disease compared with those who took a placebo.

———————————-

http://www.internalmedicinenews.com/specialty-focus/oncology-hematology/single-article-page/estrogen-protects-against-breast-cancer-long-after-treatment.html

66) Estrogen Protects Against Breast Cancer Long After Treatment  By: MARY ANN MOON, Internal Medicine News Digital Network

(Link removed)
Estrogen-only RT continues to protect women against breast cancer long after they have stopped March 6, 2012 in Cancer

Women who use the oestrogen-only form of hormone replacement therapy (RT) appear less likely to develop breast cancer in the longer term, according to new research published Online First in The Lancet Oncology. A follow-up study of over 7500 women from the Women’s Health Initiative (WHI) trial who took oestrogen for about 6 years and then stopped has found that they are over 20% less likely to develop breast cancer and remain significantly less likely to die from the disease than those who never used RT, a period of nearly 5 years after stopping treatment.

67) http://well.blogs.nytimes.com/2011/04/05/estrogen-lowers-risk-of-heart-attack-and-breast-cancer-in-some/  Estrogen Lowers Breast Cancer and Heart Attack Risk in Some By TARA PARKER-POPE  April 5, 2011, 4:02 pm

Dr. Chlebowski previously led research that showed cancer risks associated with combination hormone therapy, but he says the new data on estrogen alone show that in certain women, estrogen use to relieve menopausal symptoms is a “good choice.”

68) http://www.cbsnews.com/8301-504763_162-57392262-10391704/estrogen-pills-reduce-breast-cancer-risk-in-study-of-menopausal-women/
Estrogen pills reduce breast cancer risk in study of menopausal women  By   CBS News Staff

“Estrogen on its own appears to be safe,” said Dr. Anthony Howell, professor of medical oncology at the University of Manchester, who co-authored a commentary in the same issue.

69) http://www.suzannesomers.com/Blog/post/My-Response-to-New-York-Times-Blog-by-Tara-Pope.aspx

My Response to New York Times Article by Tara Pope  by Suzanne Somers 4/6/2011 2:43:00 PM

Hi Friends,   This is my response to Tara Pope’s article yesterday in the New York Times.  I have no idea if they will print my letter but I thought you’d like my perspective.  Her article follows my response.   Ms. Pope ignores the existence of biodidentical hormone replacement therapy.

Estrogen Lowers Breast Cancer Risk In Some Women By MARIA CHENG   03/ 6/12

70) http://www.drugs.com/news/estrogen-only-therapy-may-reduce-breast-cancer-risk-36841.html

Estrogen-Only Therapy May Reduce Breast Cancer Risk TUESDAY March 6, 2012 — Some women who take estrogen-only hormone replacement therapy to stave off hot flashes, night sweats and other symptoms of menopause may be at lower risk for developing breast cancer down the road, a news study says.

71) http://kwgn.com/2012/03/08/study-estrogen-treatment-may-protect-against-breast-cancer-5/
Study: Estrogen treatment may protect against breast cancer  March 8, 2012, by Nina Sparano

DENVER — Estrogen, a hormone known to fuel breast cancer, may actually protect against the disease. According to a new study women taking Hormone Replacement Therapy (RT) are more than 20-percent less likely to develop breast cancer and had a reduced risk of dying from the disease.More than 7,600 women taking RT were studied. Women who took estrogen-only for six years and then stopped taking the hormone showed the reduced risk.

The new study, published in the journal Lancet Oncology, provides the strongest evidence yet that estrogen alone not only lowers breast cancer risk for a sustained time for some women but curbs the chances of dying from the disease.

A Positive Research on Estrogen and Breast Cancer Posted by hodgeroberts on March 7, 2012
Many females that consumed only estrogen as a way for hormone replacement therapy following menopause faced a lower chance of developing cancer of the breast up to 5 years after they ceased taking this, as reported in a study. The review, released recently, provides another angle to the changing story of whether hormonal replacement treatment helps a few women more than treating menopause indications for example hot flashes as well as poor rest condition.

he review is a follow up evaluation of a prior milestone of an effort in women’s health, a medical trial of thousands of females started a few years back that searched to explain the potential risks and advantages of two hormonal replacement treatment sessions within post-menopausal women: a combo of estrogen plus progestin, that nearly all women will need to take, and only estrogen, used by ladies who have gotten hysterectomies.

73) http://www.mnn.com/health/fitness-well-being/stories/breast-cancer-risk-reduced-by-estrogen-only-hormone-replacement-th
Breast cancer risk reduced by estrogen-only hormone replacement therapy
The lowered risk was not found in women with a family history of the disease, and the therapy comes with a risk of stroke and blood clots, the researchers said.
By Rachael Rettner, MyHealthNewsDailyTue, Mar 06 2012 at 6:36 PM EST

74) http://www.cancernews.us/2012/03/estrogen-therapy-helps-reduce-breast.html
Friday, March 9, 2012

Estrogen therapy helps reduce breast cancer risk in some patients

75) Dr Susan Love
http://blog.dslrf.org/?p=497
Estrogen and Breast Cancer: It’s Complicated!
The conventional wisdom is that estrogen causes breast cancer.

76)
http://www.webmd.com/breast-cancer/news/20120306/estrogen-after-hysterectomy-lowers-cancer-risk

Estrogen After Hysterectomy Lowers Cancer Risk? Experts Say the Decision to Use Hormone Replacement Is a Still Complicated One By Brenda Goodman, MA WebMD Health News

Compared to women taking a placebo, women who took estrogen had a 23% reduced risk of invasive breast cancer. That means 151 women got breast cancer in the estrogen group compared to 199 women assigned to the placebo.
Women taking estrogen also had a 63% reduced risk of dying from breast cancer compared to women on the placebo. Overall, there were six deaths in the estrogen group compared to 16 in the placebo group.

———————————–

studies which show that estrogen causes breast cancer  (????)
They included progestin use….

77) http://www.ncbi.nlm.nih.gov/pubmed/10213546
Collaborative Group on Hormonal Factors in Breast Cancer – . Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer.
Lancet. 1997;350(9084):1047–1059.
(They used RT which included synthetic progestin)

78) http://jama.ama-assn.org/content/265/15/1985.abstract
A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. Steinberg KK ,Thacker SB, Smith SJ,et al

The increase in risk was largely due to results of studies that included premenopausal women or women using estradiol (with or without progestin), studies for which the estimated relative risk was 2.2 (CI, 1.4 to 3.4) after 15 years.
(Again progestins were included)

Million Womnen Study

79) http://jnci.oxfordjournals.org/content/103/4/296.full
Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy by  Valerie Beral,  Gillian Reeves,  Diana Bull,  Jane Green and  for the Million Women Study JNCI J Natl Cancer Inst (2011) 103 (4): 296-305.

Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05,
Breast cancer risk was statistically significantly increased in users of estrogen-only hormonal therapy if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51, P < .001), whereas if such use began 5 years or more after menopause, breast cancer risk was not increased (RR = 1.05, 95% CI = 0.89 to 1.24, P = .6).

among current users of estrogen–progestin formulations (RR = 1.53 )

———————————————————-

80)
2010 SABCS Interview with Rowan T. Chlebowski, M.D., Ph.D. discusses WHI Data
https://www.youtube.com/watch?v=ze2Y742NTSo

81) https://www.youtube.com/watch?v=0APKwNLC3Bk
laura esserman breast cancer video

sept 2011 mammography screening
how can it help and what are its limitations.

key is cancer biology.
Beast cancer is not one disease

=======================================================82) http://jama.ama-assn.org/content/291/14/1701.full
JAMA. 2004;291(14):1701-1712.
Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy The Women’s Health Initiative Randomized Controlled Trial ,The Women’s Health Initiative Steering Committee* Garnet L. Anderson, PhD, WHI Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M3-A410, Box 19024, Seattle, WA 98109

5200 women CEE, 5200 placebo, with 7 year follow up

Cancer. Invasive breast cancer,
23% lower rate in the CEE group than in the placebo group (26 vs 33 per 10 000 person-years)
94 CEE   124 placebo and this comparison narrowly missed statistical significance (P = .06).

Results  CEE vs placebo (average follow-up 6.8 years):
CHD, 0.91 (0.75-1.12) with 376 cases;
breast cancer, 0.77 (0.59-1.01) with 218 cases; (94 CEE and  124 placebo)
stroke, 1.39 (1.10-1.77) with 276 cases;
PE, 1.34 (0.87-2.06) with 85 cases;
colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and
hip fracture, 0.61 (0.41-0.91) with 102 cases.

http://www.ncbi.nlm.nih.gov/pubmed/10213546
Lancet. 1997 Oct 11;350(9084):1047-59.

======================================================

83)
http://jama.ama-assn.org/content/289/24/3243.short
JAMA. 2003;289(24):3243-3253
Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women The Women’s Health Initiative Randomized Trial by     Rowan T. Chlebowski, MD, PhD et al.   for the WHI Investigators

Main Outcome Measures  Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure.

Results  In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P = .003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P = .04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P = .04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration.

Conclusions  Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.

———————————————–

LOW Testosterone and Mortality from Heart Disease

84) Hyde Z, Norman PE, Flicker L, et al.  Low free testosterone predicts mortality from cardiovascular disease but not other causes: The Health in Men Study. J Clin Endocrinol Metab 2011 Endocrine Abstracts (2011) 25 P163

85)
Low testosterone predicts increased mortality and testosterone replacement therapy improves survival in men with type 2 diabetes by Vakkat Muraleedharan1,2, Hazel Marsh1 & Hugh Jones1,2 1Barnsley Hospital NHS Foundation Trust, Barnley, UK; 2University of Sheffield, Sheffield, UK.

Background: Low testosterone in men is associated with increase in all-cause and cardiovascular mortality. There is a high prevalence of hypogonadism in men with type 2 diabetes and testosterone replacement therapy (TRT) improves cardiovascular risk. However there is no published data regarding mortality in these patients in relation to testosterone levels, and the long term effect of TRT on mortality.

Aim: We report a 6 year follow-up study examining the effect of baseline testosterone and TRT in hypogonadal men with type 2 diabetes on all-cause mortality.

Methods: Five hundred eighty-seven patients with type 2 diabetes had total testosterone (TT) performed between 2002 and 2005 and were followed up for 5.8±1.3 years.

Deaths during the first 6 months were excluded. Patients were then analysed in three groups. i) normal TT (>10.4 nmol/l) ii) low TT (=10.4 nmol/l) without TRT. iii) low TT receiving TRT for 2 years or more.

Results: Of 580 patients analysed, 338 had normal TT (58%) and 240 low TT (42%). In the low TT group 58 patients received TRT. Mean age 61±11 S.D. and similarly matched in all three groups. Total deaths 72 (12.4%). Mortality rates – low TT without treatment (36/182-20%), normal TT (31/338-9%) and low TT with TRT (5/58-8.6%). Survival was significantly decreased in patients with low TT without TRT (P=0.001 log rank) compared to normal. The treated group had improved survival (P=0.049 log rank). In the Cox Regression model multi-variate (age, weight, HbA1c, pre existing cardiovascular disease, smoking, statin and ACEi/ARB use) adjusted hazard ratio for all-cause mortality was 2.2 (95% CI 1.3–3.7 P=0.001) for low TT.

Conclusions: This study shows that men with type 2 diabetes and low testosterone have a significant increased mortality. TRT improved survival compared to those untreated, recording a similar mortality rate to the normal TT group.

EPIC Study

86) Circulation. 2007;116:2694-2701. Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men. European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Kay-Tee Khaw, MBBChir, FRCP; Mitch Dowsett, PhD; Elizabeth Folkerd, PhD; Sheila Bingham, PhD; Nicholas Wareham, MBBS, PhD; Robert Luben, BSc; Ailsa Welch, PhD; Nicholas Day, PhD

Male Veterans

87) Low Serum Testosterone and Mortality in Male Veterans Arch Intern Med. 2006;166:1660-1665 Molly M. Shores, MD; Alvin M. Matsumoto, MD; Kevin L. Sloan, MD; Daniel R. Kivlahan, PhD .

88) The Journal of Clinical Endocrinology & Metabolism 2008 Jan;93(1):68-75.  Low Serum Testosterone and Mortality in Older Men. Gail A. Laughlin, Elizabeth Barrett-Connor and Jaclyn Bergstrom.

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Bioidentical Hormone Estrogen Prevents Heart Disease
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Bioidentical Hormone Estrogen Prevents Heart Disease
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Bioidentical Hormone Estrogen Prevents Heart Disease
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About Jeffrey Dach MD

Medical Director of TrueMedMD, a Clinic in Davie Florida specializing in Bioidentical Hormones and Natural thyroid. Office address 7450 Griffin Road Suite 190, Davie, Florida 33314 telephone 954-792-4663

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