The Fear of Estrogen Part Two by Jeffrey Dach MD (2024)

The Fear of Estrogen Part Two by Jeffrey Dach MD

In part one of this series, we discussed how fear of estrogen is one of the errors of modern medicine, causing increased mortality and suffering in large numbers of menopausal women by denying them HRT (hormone replacement). To be fair, we should present the other side of the argument, and try to understand the views and positions of the other side, the estrogen denialists such as Dr. Adriane Fugh-Berman who speaks and writes extensively against the use of estrogen for menopausal women. (4)

Above Header Image Courtesy of Wikimedia Commons, “Menopause”, Kibbutz Hagoshrim November 2011 Source Avishai Teicher via the PikiWiki – Israel free image collection project. CC 2.5

Dr. Adriane Fugh-Berman Opposition to Use of Estrogen

Firstly I must admit I greatly respect and admire Dr. Adriane Fugh-Berman who graduated from Georgetown University School of Medicine and completed a family medicine internship at Montefiore Hospital in the Bronx. She is currently Professor of Pharmacology & Physiology in the Department of Family Medicine at Georgetown University Medical Center. (1-2)

I suggest Dr. Berman is a “medical thought leader” and menopausal women look to her for advice. I must say I agree with many of her statements, such as those on the corrupting influence of the pharmaceutical industry on the practice of medicine, ghost writing, disease mongering etc. However, I would respectfully disagree with Dr. Berman’s opposition to menopausal hormone replacement expressed in her 2002 book, The Truth about Hormone Replacement Therapy : How to Break Free from the Medical Myths of Menopause. On the Amazon page for the book, Dr. Adrienne Fugh-Berman writes:

Menopause is not a disease.So why are millions of American women taking a drug [estrogen] for this natural body process? The widespread popularity of hormone replacement therapy (HRT) is a triumph of marketing and advertising over science. Although HRT and estrogen replacement therapy (ERT) can help some women with certain menopause-related problems, the benefits have been oversold to women and their health care providers. There is no scientifically valid evidence that estrogen prevents heart disease, colon cancer, or Alzheimer’s. Nor is there any evidence that it keeps you looking younger, preserves your sex drive, or enhances your memory. However, HRT does carry the risk of serious side effects, including certain cancers. Should you be taking such risky drugs to help you get through menopause? (3)

I would suggest the above views are in error as there are many scientifically valid studies showing estrogen prevents heart disease such as the 2012 RCT (randomized controlled trial), the Danish Osteoporosis Prevention study (Schierbeck,DOPS, 2012) which showed a 52% reduction in death, admission to hospital for heart failure, and myocardial infarction in the hormone treated group. Women on HRT enjoy a 63 percent reduction in colon cancer (Rennert, 2009), and the WHI (first arm, CEE+MPA) report 28 percent reduction in risk for colon cancer. Preclinical and clinical studies show estrogen and progesterone are neuroprotective with improvement in memory and cognition. There is considerable evidence of improved sex drive (libido) with HRT, especially the using the testosterone component. (7-14) (27)

Progesterone has remarkable anti-cancer effects and is mainstream conventional treatment for prevention of endometrial/ uterine cancer. Progesterone studies also show remarkable efficacy in prevention and treatment of other cancers, breast, endometrial/uterine, ovarian cancer, prostate cancer, colon, non-small-cell lung cancer, malignant melanoma and mesothelioma. (27)

Her Turn News Podcast 2023

In a December 2023 interview recorded as a podcast on Arlene Zaucha’s Her Turn News, Dr. Berman expresses many of her opposing views on menopausal hormone replacement, firstly claiming “menopause is not a disease”. I would disagree with this statement. Menopause is an estrogen deficiency disease which then leads to degeneration in all estrogen dependent organs and body tissues. Dr. Berman would than call this “normal aging”. If this is true, then other hormone deficiency diseases such as Addison’s, Type One Diabetes, and Hypothyroidism are all normal aging events that should not be treated with the missing hormones, cortisol, insulin and thyroid hormones. Of course we know this would not be acceptable to anyone. In my opinion, as discussed elsewhere in this book, estrogen deficiency leads to a number of degenerative diseases, such as cardiovascular disease, osteoarthritis, osteoporosis, retinal and neural degeneration, cognitive impairment, and genito-urinary syndrome with recurrent UTI’s as discussed in the Chapter on the Health Benefits of Estrogen Hormone Replacement. In my opinion, menopausal women should be offered treatment with natural human bioidentical HRT providing them with reduced mortality and a better quality of life. Menopausal HRT should be a basic tenet of OB/Gyne and family practice medicine. For the subspecialties of cardiology, rheumatology, orthopedics, neurology, and psychiatry, these specialist doctors should be prescribing HRT for their menopausal patients or at least referring them to a physician who can. How can we explain Dr. Berman’s negative attitude regarding menopausal hormone replacement? Perhaps the most significant factor is Dr. Berman does not practice medicine herself. She does not have first hand experience with menopausal women’s complaints on a day to day basis. If she treated menopausal patients, she would find her patients responding to menopausal hormone replacement by reporting symptomatic relief, and improved quality of life. Many will express gratitude. Let’s review a few of Dr. Berman’s statements in this podcast interview which targets hormone replacement for menopausal women. My response to Dr. Berman’s statement are indented. (4)

Dr. Berman : There is no medical test for menopause.

My reply: No medical test is needed since medical history of cessation of menses indicates menopause. However, in some patients a medical test would be useful, such as women who have had partial hysterectomies with removal of uterus with preservation of ovaries. In this case, marked elevation of LH and FSH hormones is a useful test indicating menopausal status, characterized by ovarian failure with low serum estrogen levels.

Dr. Berman: The only symptoms proven to be associated with menopause is hot flashes and night sweats and vagin*l dryness. Most menopausal symptoms are the result of aging. In Japan, menopause is associated with joint pain.

My reply: Hot flashes, night sweats and vagin*l dryness are indeed the three most often and glaring symptoms of menopause brought to medical attention. Menopausal estrogen deficiency causes joint pain and osteoarthritis not only in Japan, but also the in the U.S. and rest of the world. Many other menopausal symptoms are related to degeneration of organs and tissues resulting from estrogen deficiency such as osteoarthritis, osteoporosis with fracture risk, insomnia, mood disturbance, loss of libido, vagin*l atrophy and vulvo-vagin*l syndrome (chronic UTI’s), Type II diabetes, retinal degeneration, and cognitive dysfunction. To say estrogen deficiency of menopause is normal aging, and deny women estrogen treatment for menopausal symptoms is not a good idea. Why not treat these menopausal women with the most effective treatment, estrogen hormone replacement, and alleviate misery and suffering in this patient population?

Dr. Berman : estrogen alone resulted in endometrial cancer.

My reply: This is correct and I agree with Dr. Berman. There is no argument here. However, one must be careful and say it is the unopposed estrogen which causes endometrial hyperplasia and increases risk for endometrial cancer. Micronized progesterone is FDA approved for prevention of endometrial hyperplasia, and when progesterone is combined with estrogen, there is no increased risk of endometrial cancer. In the WHI study (first arm CEE+MPA) after 5.2 years, there was 17 percent reduction in endometrial cancer in the hormone treated group. (14-16)

Dr. Berman: Later on, hormones came back with a progestin added. This was meant to prevent heart disease, stroke, dementia.

My reply: Dr. Fugh-Berman’s makes three errors here. The first error is lumping together progestins with progesterone, and not differentiating between the two. The progestins such as medroxyprogestroeen (MPA) are the cause of poor health outcomes, while human bioidentical progesterone is the preferred choice, having better outcomes. Error number two is not explaining that oral estrogens cause increased coagulation and clotting, leading to DVT and stroke, while the transdermal route of delivery of estrogen does not cause clotting and stroke and is the preferred choice, avoiding the oral estrogen route of administration. The third error is not mentioning the “Timing Hypothesis” of Drs. Howard Hodis and Wendy Mack which is that estrogen reduces heart attacks by 46 percent in the younger 50-60 age group as demonstrated in the 2011 WHI (second arm, estrogen alone) and more recently, in the 2012, the Danish Osteoporosis Prevention study, (DOPS RCT) study in which women receiving hormone therapy (HT) had a 52 percent reduced risk of composite cardiovascular safety outcomes, death, or hospitalization for MI or heart failure (hazard ratio [HR], 0.48) (Cho, Leslie, 2023) (Schierbeck, 2012). However, in older women starting HRT more than 10 years after menopause transition, the studies show no cardiovascular benefit (null effect). (17-18) (28)

Dr. Berman: HERS Trial tested hormones in women who had had a heart attack. It was found there was no beneficial effect at al.

My reply: I agree with Dr. Berman. The Hers Trial used oral premarin and MPA (medroxyprogestreone) in older women with known coronary artery disease showing no cardiovascular benefit. We do not use this hormone combination of horse estrogen with a synthetic progestin. This combination is not actually women’s ovarian hormone replacement, and should never be used. Dr. Berman fails to mention that later studies such as the WHI second arm , the 2012 DOPS, KEEPS and ELITE studies all showed cardiovascular benefit of natural, ovarian hormone replacement. Dr. Berman also fails to mention that animal and human studies show cardiovascular benefit when HRT is started early, shortly after the menopausal transition. Estrogen can not reverse the established coronary artery plaques in older post menopausal women starting HRT 10 years after menopausal transition. However it is preventive before the plaques form. The message here that Dr. Berman should be advising menopausal women to start HRT early, and not to wait. (19-22)

Dr. Berman : The WHI clinical trial NIH funded under director Bernadine Healy. This trial found the risks far outweigh the benefit for menopausal hormone therapy.

Again, Dr Berman ignores and fails to mention the second arm of the WHI estrogen alone which showed women in the 50-59 age group enjoyed dramatic reduction in mortality, myocardial infarction and heart disease risk. Dr Fugh-Berman fails to recognize the poor outcomes were seen in the first arm, associated with older age group, and use of oral estrogen (CEE) and synthetic progestins (MPA). See: Estrogen Prevents Coronary Artery Disease.

Dr. Berman: In terms of disease prevention, hormones should never be used for disease prevention.

This is an error. Dr. Berman is stating that hormone deficiency is not a disease. Let me ask you this: Why is it that other forms of hormone deficiency are accepted by mainstream medicine as diseases, yet Dr. Berman claims estrogen deficiency is not a disease? Insulin deficiency is found in Type One Diabetes. This is treated with a hormone called insulin. Cortisol deficiency is Addison’s disease treated with another hormone called cortisol. Thyroid deficiency is hypothyroidism, a disease treated with thyroid hormone. As mentioned above, menopausal estrogen deficiency is a disease leading to degeneration of estrogen dependent organs and tissues. Menopausal HRT with natural, human (bioidentical) estrogen, progesterone, testosterone should be used for prevention and treatment of osteoarthritis, osteoporosis, coronary artery disease, genito-urinary syndrome, dementia, and macular degeneration. and Type II Diabetes.

Dr. Berman : Women should stop HRT when hot flashes stop.

This is an error. I advise women to continue HRT even after complete symptom relief to prevent onset of estrogen deficiency diseases as listed above, osteoarthriits, osteoporosis, coronary artery disease, cognitive dysfunction, vagin*l dryness and genito-urinary syndrome, Type II Diabetes, etc.

Dr. Berman : Estrogen increases blood clots.

I agree with this statement. However, this applies to oral estrogen, and not transdermal delivery of estrogen. Dr. Berman fails to advise women to avoid oral estrogen and instead use the transdermal delivery of estrogen which is safer and avoids the blood clotting effects of oral estrogen. See Transdermal Vs. Oral Estrogen part two.

Dr. Berman: This idea that breast cancer risk is low. There is really no question that hormone therapy increases breast cancer risk.

I agree with Dr. Berman that the WHI first arm revealed increased breast cancer risk with the combination of oral estrogen (CEE) and MPA, a synthetic chemically altered version of progesterone. However, Dr Fugh-Berman fails to recognize and mention the 23 percent reduction in breast cancer in the WHI (second arm, estrogen alone). And Dr. Berman also fails to mention the 45 percent reduction in mortality from breast cancer in the 18 year follow up of this estrogen alone group. Most of her listening audience would want to know this.

Dr. Berman: If you are not having hot flashes, you don’t need medication of any sort.

Dr. Berman fails to recognize menopausal estrogen deficiency as a disease leading to degeneration of estrogen dependent organs and tissues. All post menopausal women should be offered natural human bioidentical hormone replacement. See: Health Benefits of Menopausal Hormone Replacement

Dr. Berman: Symptoms associated with menopause are not caused by menopause. They are caused by aging.

This is a nonsensical statement equivalent to stating symptoms of hypothyroidism are caused by aging, and therefore should not be treated. Symptoms of menopause are caused by menopausal estrogen deficiency, and untreated menopausal women are subject to increased mortality and a host of degenerative diseases. They deserve better care than calling this “aging”.

Dr. Berman: Medicalization of menopause is an industry funded campaign.

I agree with the above statement by Dr. Berman. This is called disease mongering, the medicalization of symptoms in order to create a new disease to sell a drug, merely a standard marketing practice by the drug industry. An example of this is labeling normal children as ADHD and then treating them with addictive amphetamines having the same mechanism of action as cocaine (Ritalin, Adderal, etc). In 2005, Dr. Howard Wolinsky writes:

routine human conditions—unhappiness, bone thinning, stomach aches and boredom—is increasingly being re-defined as disease: depression in its milder forms, osteoporosis, irritable bowel syndrome and attention deficit disorder. Likewise, risks factors, such as high cholesterol and high blood pressure, are declared diseases in their own right—hypercholesterolaemia and hypertension—with falling thresholds resulting in more people considered to be sick. In other cases, drugs approved for devastating illness, such as clinical depression, are indicated for milder conditions, such as shyness, which is now dubbed ‘social phobia’. (23-26)

However, in the case of menopausal symptoms treated with hormone replacement, Dr. Berman’s label of drug mongering or medicalization is not justified and quite off the mark. See: The ADHD Drug Epidemic, Amphetamines and Methylphenidate.

Dr. Berman: Low doses of antidepressant can be helpful in menopause.

It is quite surprising that Dr. Berman is usually “anti-drug industry”, yet in the above statement promotes the use of SSRI antidepressants for a hormone deficiency state. SSRI antidepressant drugs do not contain estrogen and are ineffective as a treatment for menopausal estrogen deficiency. Not only that, these drugs carry adverse side effects of emotional blunting, loss of libido and can induce psychotic or violent behavior. My advice to all women is to stay away from SSRI antidepressants, use the real thing, bioidentical hormones for the best results. See: Paxil for Hot Flashes, A Cruel Joke?

Dr. Berman: phytoestrogens in soybeans can be helpful for menopausal symptoms.

Since Dr. Berman is opposed to the use of hormone replacement, what is the symptomatic menopausal women to do? It is just sad to me that any medical thought leader would propose phytoestrogens in soy products as an effective treatment for menopausal symptoms of estrogen deficiency. The idea of soy for menopause originated in Japan where fermented soy products in the Japanese diet were thought to explain the reduction in hot flashes in Japanese menopausal women. However U.S. soy is genetically modified (round-up ready) and treated with massive amounts of glyphosate herbicide. These residues end up in the food. Since 1995, there have been over 50 clinical trials of soy extracts, not with soy foods or soy protein products, which studied them for relief of hot flashes. In 2012, Dr. Kyoko Taku writes: “Two reviews and meta-analyses have concluded that soy isoflavones alleviate hot flashes; however, most of the others have stated that the data are not sufficiently conclusive to allow definitive conclusions to be made.” Soy phytoestrogens are weak agonists of the estrogen receptor, and paradoxical results may be obtained. In some products and patients, ER signalling is enhanced, and in other cases, ER signalling is blocked, making menopausal symptoms worse. I have seen this with women consuming soy protein bars. See: A Mysterious Return of Menopausal Symptoms, Soy Phytoestrogens. The doctor who discovered the ER-Beta receptor Jan-Ake Gustafsson in Houston is interested in soy isoflavones extracts as ER-Beta agonists thinking they might have future use as anticancer agents. Again, we find the same problem, paradoxical activity. Soy phytoestrogens bind with higher affinity to ER-Beta (cancer-protective), but at higher doses they bind with higher affinity to ER Alpha (pro-carcinogenic). Better to use real estrogen in a form called estriol (E3) which binds 90% to ER-Beta, and testosterone whose metabolite binds preferentially to ER Beta. In 2022, Dr. Margaret Warner writes:

Although phytoestrogens bind with a higher affinity to ERβ [Estrogen Receptor Beta] than ERα [Estrogen Receptor Alpha] they are not dispensed clinically, because at high doses they can activate ERα. (4) (29-35)

Conclusion: In order to take a position opposed to the use of hormone replacement for menopausal women, one must ignore much of the medical literature on hormone replacement. Doing so usually involves believing that only RCT’s randomized controlled trials can be used as evidence, yet discarding those RCT’s that conflict with one’s position. Preclinical, animal and observational studies are all valid as scientific evidence and should be included in one’s knowledge base. When viewing the totality of the medical literature on this topic over more than 100 years, one comes to the overwhelming conclusion that natural bioidentical menopausal hormone replacement is the cornerstone for healthy menopause. When it comes to the practice of medicine, nothing is more gratifying to the doctor than prescribing menopausal hormone replacement. The dramatic improvement in quality of life we see in the patient is simply miraculous. What else in medicine can compare to this? Perhaps modern cataract surgery with lens implant with its dramatic recovery of vision comes close. My advice to Dr. Berman is this: Try prescribing HRT for your menopausal patients, after you get the appropriate training. You will be pleasantly surprised with the results.

Articles with Related Interest:

Estrogen Prevents Coronary Artery Disease

Errors in Modern Medicine: The Fear of Estrogen Part One

Health Benefits of Menopausal Hormone Replacement

SSRI Drugs for Menopausal Symptoms, Surely You Are Joking?

All Bioidentical Hormone Articles

References:

1) Adriane Fugh-Berman Professor of Pharmacology & Physiology M.D.
Georgetown University, 1988 The primary areas of research for Dr. Fugh-Berman are pharmaceutical marketing practices and the culture of medicine. She directs PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices. Dr Fugh Berman also studies the benefits and risks of complementary and alternative medicine (CAM), especially herbs and dietary supplements. She has a particular interest in herb-drug interactions. Dr. Fugh-Berman maintains medicinal herb gardens on the Georgetown campus, and directs the Urban Herbs project.

2) Adriane J Fugh-Berman SOM Medical Educator Track — Professor
Bio and Featured Works

Adriane Fugh-Berman, MD is a Professor of Pharmacology and Physiology with a joint appointment in the Department of Family Medicine at Georgetown University Medical Center. Dr. Fugh-Berman co-directs the M.S. program in Health and the Public Interest and directs PharmedOut, a GUMC research and education project that promotes rational prescribing, exposes the effect of pharmaceutical marketing on prescribing practices and has had a profound impact on prescribers’ perceptions of the adverse consequences of industry marketing.
Previously, Dr. Fugh-Berman was a medical officer in the Contraception and Reproductive Health Branch of the National Institute for Child Health and Human Development, NIH. She has also worked with the nonprofit Reproductive Toxicology Center and edited an award-winning CME newsletter on women’s health.

Dr. Fugh-Berman graduated from Georgetown University School of Medicine and completed a family medicine internship in the Residency Program in Social Medicine at Montefiore Hospital in the Bronx.

3) The Truth about Hormone Replacement Therapy : How to Break Free from the Medical Myths of Menopause by Adrienne Fugh-Berman and National Women’s Network Staff (2002, Trade Paperback) Dr. Berman writes:

Menopause is not a disease.So why are millions of American women taking a drug [estrogen] for this natural body process? The widespread popularity of hormone replacement therapy (HRT) is a triumph of marketing and advertising over science. Although HRT and estrogen replacement therapy (ERT) can help some women with certain menopause-related problems, the benefits have been oversold to women and their health care providers. There is no scientifically valid evidence that estrogen prevents heart disease, colon cancer, or Alzheimer’s. Nor is there any evidence that it keeps you looking younger, preserves your sex drive, or enhances your memory. However, HRT does carry the risk of serious side effects, including certain cancers. Should you be taking such risky drugs to help you get through menopause?

Menopause is not a disease.So why are millions of American women taking a drug for this natural body process? The widespread popularity of hormone replacement therapy (HRT) is a triumph of marketing and advertising over science. Although HRT and estrogen replacement therapy (ERT) can help some women with certain menopause-related problems, the benefits have been oversold to women and their health care providers. There is no scientifically

The authors disagree with the widely promoted message that nearly all perimenopausal women should use HRT for cardiovascular and bone health or to modulate health problems associated with that stage of life; they argue that, except for a very small percentage of women, using alternative therapies is preferred. They also report on studies of HRT and provide a wealth of information. While their analytical and cautious approach is commendable, their words are often provocative e.g., they claim that the drug companies “play on women’s fears,” utilize “scare tactics,” and “artfully persuade.” Within the profusion of books on HRT on the market today, this one stands out not because of its advocacy of alternative treatments but because it is so vehement in its criticism of the medical and pharmaceutical establishments.

4) Menopause is not a disease. December 10, 2023 by Her Turn News podcast audio recording of interview. Link using Wayback Machine

Here’s a news ‘hot flash’ for you: menopause is not a disease. Menopause is not a disability — but you might think so if you’ve been paying attention to the new marketing push targeting mid-life women. We have a feminist take on the natural process for mid-life women. Her Turn reporter Arlene Zaucha talks to a longtime feminist health activist Dr, Adriane Fugh Berman about the issue. Dr. Fugh Berman runs Pharmed Out, which has more information at pharmedout.org.

Errors

1) Dr. Berman : There is no medical test for menopause.

Marked elevation of LH and FSH hormones indicates menopausal state characterized by ovarian failure and low estrogen levels.

Dr. Berman : The only symptoms proven to be associated with menopause is hot flashes and night sweats and vagin*l dryness. Most menopausal symptoms are the result of aging. In Japan, menopause is associated with joint pain.

estrogen deficiency also causes joint pain, osteoarthritis, bone loss, osteoporosis, increased fracture risk, insomnia, loss of libido, vagin*l atrophy and vulvo-vagin*l syndrome.
(chronic UTI’s)

Dr. Berman : estrogen alone resulted in endometrial cancer.

This is correct

Dr. Berman : Later on , hormones came back with a progestin added. This was meant to prevent heart disease, stroke, dementia. All things we now know hormones dont health and in fact increase.

Dr Fugh-Berman’s error is lumping together Progestins with progesterone, and not differentiating between the two. The progestins are the cause of poor health outcomes, while human bioidentical hormones estrogen are associated with good health outcomes.

Dr. Berman : HERS Trial tested hormones in women who had had a heart attack. It was found there was no beneficial effect at al.

Dr. Berman : WHI clinical trial NIH funded under Bernadine Healy. This trial found the risks far outweigh the benefit for menopausal hormone therapy.

Again, Dr Fugh-Berman fails to recognize the poor outcomes were from use of synthetic progestins in the WHI. Dr Berman ingnores the second arm of the WHI estrogen alone which showed women in the 50-59 age group enjoyed dramatic reduction in myocardial infarction and heart disease risk.

Dr. Berman’s Error: “In terms of disease prevention, Hormones should never be used for disease prevention.”

This is wrong. Bioidentical Hormones, estrogen, progesterone, testosterone are used, and should be used to prevent estrogen deficiency diseases of osteoarthritis, osteoporosis, heart disease, and dementia, macular degeneration and cancer prevention.

Dr. Berman : “Women should stop HRT when hot flashes stop.” This is an error.

Dr. Berman : Error:”Estrogen increases blood clots”

Oral estrogen does,. Transdermal does not. Failure to say transdermal estrogen does not increase blood clots and is preferred over oral estrogen.

New York times criticized the WHI study.

“all these ctiticisms are from the industry?

Error: Dr Fugh-Berman fails to recognize and mention the positive health outcomes of the 2nd arm (premarin alone) WHI study.

Dr. Berman : Error: “This idea that breast cancer risk is low. There is really no question that hormone therapy increases breast cancer risk.

Dr Fugh-Berman fails to recognize and mention the reduction in breast cancer in the premarin alone group. And the increased breast cancer in the progestin users.

Dr. Berman : Error: if you are not having hot flashes, you dont need medication of any sort.

Dr. Berman : Error: Symptoms associated with menopause are not caused by menopause. They are caused by aging.

Dr. Berman : Medicalization of menopause is an industry funded campaign.

This is true, as this is a standard marketing practice by the pharmaceutical industry for all drugs.

Dr. Berman : Error: Low doses of antidepressant can be helpful in menopause.

Dr. Berman : Error: phytoestrogens in soybeans can be helpful for menopausal symptoms.

Dr. Berman : Error: Hormones dont work for everyone either.

Dr. Berman : Error: vagin*l dryness can be dealt with moisturizers or topical estrogen.

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free pdf

5) Fugh-Berman, Adriane. “The science of marketing: How pharmaceutical companies manipulated medical discourse on menopause.” Women’s Reproductive Health 2.1 (2015): 18-23.

The case is closed. Women without symptoms should not use HT [hormones therapy]. Women with symptoms should carefully weigh benefits against risks, and, if they choose to take hormones, they should take as little as possible for as short a time as possible.

!!!!!!!!!!!!!!!!!!!!! GOOD !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

6) Fugh-Berman, Adriane, and Anthony R. Scialli. “Gynecologists and estrogen: an affair of the heart.” Perspectives in biology and medicine 49.1 (2006): 115-130.

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7) Hodis, Howard N., and Wendy J. Mack. “Menopausal hormone replacement therapy and reduction of all-cause mortality and cardiovascular disease: it is about time and timing.” The Cancer Journal 28.3 (2022): 208-223.

Taken together, randomized controlled atherosclerosis imaging trials and animal studies strongly support the healthy endothelium hypothesis showing that HRT is more effective in maintaining vascular health rather than treating established vascular disease manifested as atherosclerosis lesions.

In two meta-analyses, Salpeter, et al. showed that relative to placebo, HRT significantly reduced all-cause mortality by 39% (95% confidence interval (CI), 5%–61%) across 30 RCTs and reduced CHD by 32% (95% CI, 4%–52%) across 23 RCTs when initiated in women <60 years of age and/or <10 years-since-menopause (Fig. 6) (24,25). On the other hand, the effect of HRT on all-cause mortality and CHD was null when initiated in women >60 years old and/or >10 years-since-menopause.

DOPS is the only randomized clinical event trial to closely replicate the populations of women in observational studies.

Schierbeck, Louise Lind, et al. “Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.” Bmj 345 (2012).

Women in DOPS were on average 50 years of age and 7 months past menopause with an average BMI of 25.2 kg/m2 when randomized to HRT or no HRT.

In addition, DOPS provides the longest duration of randomized HRT than any other RCT to date. CVD was reduced by 52% (hazard ratio (HR), 0.48; 95% CI, 0.27–0.89) after 10 years of randomized HRT compared with no HRT and reduced by 39% (HR, 0.61; 95% CI, 0.39–0.94) after 16 years of total follow-up (10 years of randomized treatment and 6 years of postintervention follow-up) (Fig. 8). All-cause mortality was reduced by 43% (HR, 0.57; 95% CI, 0.30–1.08) after 10 years of randomized HRT and by 34% (HR, 0.66; 95% CI, 0.41–1.08) after 16 years of total follow-up (22).

The Salpeter, et al. meta-analyses were validated and confirmed by the Cochrane group, who also showed similar reductions in all-cause mortality (30%; 95% CI, 5% – 48%) and CHD (48%; 95% CI, 4% – 71%) in women initiating HRT <60 years old and/or <10 years-since-menopause (Fig. 7) (26).

The null effect of statin therapy on primary CVD prevention in women contrasts with that of men. With careful separation of women from men and primary from secondary prevention trials, the first sex-specific meta-analysis to analyze primary CVD prevention trials showed that statin therapy reduced CHD in men but not in women (Fig. 15, top panel) (34). All-cause mortality was neither reduced in men nor women in primary CVD prevention RCTs. This latter meta-analysis included the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) trial in which 5,356 women were treated for more than 5 years (35).

The most recent primary CVD prevention RCT with statin therapy conducted in a large cohort of 5,874 women, the Heart Outcomes Prevention Evaluation-3 (HOPE-3 trial), is consistent with the sex-specific meta-analyses showing that statin therapy significantly reduces CHD in men but does not statistically significantly reduce CHD in women in primary CVD prevention and has no effect on all-cause mortality in either sex

The consistency across individual primary CVD prevention RCTs and sex-specific meta-analyses shows that statin therapy does not statistically significantly reduce all-cause mortality or CHD in women when administered for primary CVD prevention.

On the other hand, HRT is well-known to reduce new onset diabetes mellitus by 20%–30% (Fig. 18). The anti-diabetogenic effect of HRT has been shown across many independent RCTs and meta-analyses including an analysis of 107 RCTs (68–71).

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
menopausal HRT is unique in that it reduces all-cause mortality and CVD when initiated in women <60 years of age and/or <10 years-since-menopause. These cumulated findings from RCTs are consistent with the large body of observational studies that consistently show a reduction of all-cause mortality and CVD in young women who initiate HRT at the time of menopause. When initiated in women in their 50s and continued for 5–30 years, HRT reduces all-cause mortality and cost-effectively increases quality adjusted life-years (QALYs)

8) Schierbeck, L. “Primary prevention of cardiovascular disease with hormone replacement therapy.” Climacteric 18.4 (2015): 492-497.

9) Rennert, Gad, et al. “Use of hormone replacement therapy and the risk of colorectal cancer.” Journal of clinical oncology 27.27 (2009): 4542.

10) 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).

11) Salinero, Abigail E., et al. “Brain Specific Estrogen Ameliorates Cognitive Effects of Surgical Menopause in Mice.” bioRxiv (2023).

12) Russell, Jason K., Carrie K. Jones, and Paul A. Newhouse. “The role of estrogen in brain and cognitive aging.” Neurotherapeutics 16 (2019): 649-665.

13) Uloko, Maria, et al. “The clinical management of testosterone replacement therapy in postmenopausal women with hypoactive sexual desire disorder: a review.” International journal of impotence research 34.7 (2022): 635-641.

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14) Writing Group for the Women’s Health Initiative Investigators. “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.

15) Cagnacci, Angelo, and Martina Venier. “The controversial history of hormone replacement therapy.” Medicina 55.9 (2019): 602.

16) Woodruff, J. Donald, James H. Pickar, and Menopause Study Group. “Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone.” American Journal of Obstetrics and Gynecology 170.5 (1994): 1213-1223.

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17) Cho, Leslie, et al. “Rethinking menopausal hormone therapy: for whom, what, when, and how long?.” Circulation 147.7 (2023): 597-610.

18) Schierbeck, Louise Lind, et al. “Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.” Bmj 345 (2012).

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19) Grady, D., Herrington, D., Bittner, V., et al. (2002). Cardiovascular disease outcomes during 6.8 years of hormone therapy heart and estrogen/progestin replacement study follow-up (HERS II). Journal of the American Medical Association, 288, 49–57.

20) Hulley, S., Furberg, C., Barrent-Connor, E., et al. (2002). Noncardiovascular disease outcomes during 6.8 years of hormone therapy heart and estrogen/progestin replacement study follow-up (HERS II). Journal of the American Medical Association, 288, 58–66.

21) Grady, D., Applegate, W., Bush, T. L., et al. (1998). Heart and estrogen/progestin replacement study (HERS): Design, methods and baseline characteristics. Controlled Clinical Trials, 19, 314–335.

22) Hulley, S., Grady, D., Bush, T., et al. (1998). Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Journal of the American Medical Association, 280, 605–613.

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23) Wolinsky, Howard. “Disease mongering and drug marketing: Does the pharmaceutical industry manufacture diseases as well as drugs?.” EMBO reports 6.7 (2005): 612-614.

24) Kaczmarek, Emilia. “Promoting diseases to promote drugs: the role of the pharmaceutical industry in fostering good and bad medicalization.” British Journal of Clinical Pharmacology 88.1 (2022): 34-39.

25) Cetel, Jason S. “Disease-branding and drug-mongering: Could pharmaceutical industry promotional practices result in tort liability.” Seton Hall L. Rev. 42 (2012): 643.

26) Moynihan, Ray, et al. “Selling sickness: the pharmaceutical industry and disease mongering Commentary: Medicalisation of risk factors.” Bmj 324.7342 (2002): 886-891.

27) Lieberman, Allan, and Luke Curtis. “In defense of progesterone: a review of the literature.” Alternative Therapies in Health & Medicine 23.7 (2017).

28) Hodis, Howard N., and Wendy J. Mack. “Menopausal hormone replacement therapy and reduction of all-cause mortality and cardiovascular disease: it is about time and timing.” The Cancer Journal 28.3 (2022): 208-223.

Development of substantial CVD risk after menopause provides a window of opportunity for extension of cardioprotection from endogenous estrogen in postmenopausal women with hormone replacement therapy (HRT) as a sex-specific primary preventive therapy for CVD and reduction of all-cause mortality.

HRT is more effective in maintaining vascular health rather than treating established vascular disease manifested as atherosclerosis lesions.

More than 40 observational studies show a consistent 30%–50% reduction in CHD in HRT users versus nonusers

the Danish Osteoporosis Prevention Study (DOPS) is the only randomized clinical event trial specifically designed to study HRT in a cohort of recently postmenopausal women with similar characteristics to women in observational studies from which the cardioprotective hypothesis was developed (22). Similarly, the Early versus Late Intervention Trial with Estradiol (ELITE) is the only RCT specifically designed to formally test the HRT timing hypothesis in women who were randomized to HRT when <6 years and >10 years-since-menopause (23).

Totality of evidence indicates menopausal hormone replacement therapy (HRT) effects are determined by timing of initiation according to age and/or time-since-menopause, underlying health of target tissue and duration of therapy. Initiated in women <60 years of age and/or at or near menopause, HRT significantly reduces all-cause mortality and cardiovascular disease (CVD) whereas other primary CVD prevention therapies such as lipid-lowering fail to do so. Magnitude and type of HRT-associated risks, including breast cancer, stroke and venous thromboembolism are rare (<10 events/10,000 women), not unique to HRT and comparable with other medications. HRT is a sex-specific and time dependent primary CVD prevention therapy that concomitantly reduces all-cause mortality as well as other aging-related diseases with an excellent risk profile. Keeping in mind that prevention strategies must be personalized, health-care providers and patients can use cumulated HRT data in making clinical decisions concerning chronic disease prevention including CVD and mortality reduction.

Designed to specifically test the HRT timing hypothesis, ELITE showed that HRT initiated in women close in proximity to menopause reduced progression of subclinical atherosclerosis relative to placebo. In contrast, when initiated more distant from menopause, HRT had no effect on atherosclerosis progression relative to placebo

ELITE

After median 5-year intervention, women in the early postmenopause stratum (<6 ysm) showed a statistically significant reduction in progression of subclinical atherosclerosis measured by carotid artery intima-media thickness with hormone replacement therapy relative to placebo; 0.0044 versus 0.0078 mm per year (p=0.008), respectively (27).

https://www.nejm.org/doi/full/10.1056/nejmoa1505241
Hodis, Howard N., et al. “Vascular effects of early versus late postmenopausal treatment with estradiol.” New England Journal of Medicine 374.13 (2016): 1221-1231.

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nice figure 6.
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In two meta-analyses, Salpeter, et al. showed that relative to placebo, HRT significantly reduced all-cause mortality by 39% (95% confidence interval (CI), 5%–61%) across 30 RCTs and reduced CHD by 32% (95% CI, 4%–52%) across 23 RCTs when initiated in women <60 years of age and/or <10 years-since-menopause (Fig. 6) (24,25).

Further, HRT improves insulin resistance, increases glucose tolerance, and reduces new onset diabetes mellitus by 20%–30% (68–71,76).

Soy and ER-Beta Agonist –

29) Taku, Kyoko, et al. “Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials.” Menopause 19.7 (2012): 776-790.

Since the first clinical trial was conducted in 1995,17 more than 50 trials have evaluated the effects of soy foods and isoflavone-containing products on the alleviation of hot flashes.

present systematic review and meta-analysis of RCTs
was performed specifically to clarify the effects of ingesting
soy isoflavone extracts (not soy foods or soy protein) and
synthesized isoflavones on the frequency (number), severity
(intensity), and composite score (frequency severity) of hot
flashes compared with placebo as expressed as percentage
change from baseline in perimenopausal and postmenopausal
women.

Two reviews and meta-analyses have concluded that soy
isoflavones alleviate hot flashes18,19; however, most of the
others have stated that the data are not sufficiently conclusive
to allow definitive conclusions to be made.

17 trials were selected for meta-analyses to clarify the effect of soybean isoflavones on hot flash frequency (13 trials) and severity (9 trials). Metaanalysis revealed that ingestion of soy isoflavones (median, 54 mg; aglycone equivalents) for 6 weeks to 12 months
significantly reduced the frequency (combined fixed-effect and random effects model) of hot flashes by 20.6% (95%
CI, j28.38 to j12.86; P G 0.00001) compared with placebo (heterogeneity P = 0.0003, I2 = 67%; random effects
model). Meta-analysis also revealed that isoflavones significantly reduced hot flash severity by 26.2% (95% CI:
j42.23 to j10.15, P = 0.001) compared with placebo (heterogeneity, P G 0.00001, I2 = 86%; random effects model).
Isoflavone supplements providing more than 18.8 mg of genistein (the median for all studies) were more than twice as
potent at reducing hot flash frequency than lower genistein supplements.

Soy isoflavone supplements, derived by extraction or chemical synthesis, are significantly more effective than placebo in reducing the frequency and severity of hot flashes. Additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone form, baseline hot flash
frequency, and treatment duration.

30) McCarty, Mark Frederick. “Isoflavones made simple–genistein’s agonist activity for the beta-type estrogen receptor mediates their health benefits.” Medical Hypotheses 66.6 (2006): 1093-1114.

31) Bielecki, Agnieszka, et al. “Estrogen receptor-β mediates the inhibition of DLD-1 human colon adenocarcinoma cells by soy isoflavones.” Nutrition and cancer 63.1 (2011): 139-150.

32) Setchell, Kenneth DR, et al. “S-Equol, a potent ligand for estrogen receptor β, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora1–4.” The American journal of clinical nutrition 81.5 (2005): 1072-1079.

33) Messina, M. “Soyfoods and soybean phyto-oestrogens (isoflavones) as possible alternatives to hormone replacement therapy (HRT).” European Journal of Cancer 36 (2000): 71-72.

34) Wu, Wan-fu, et al. “Estrogen receptor β and treatment with a phytoestrogen are associated with inhibition of nuclear translocation of EGFR in the prostate.” Proceedings of the National Academy of Sciences 118.13 (2021): e2011269118.

35) Warner, Margaret, et al. “25 years of ERβ: a personal journey.” Journal of Molecular Endocrinology 68.1 (2022): R1-R9.

Although phytoestrogens bind with a higher affinity to ERβ than ERα they are not dispensed clinically, because at high doses they can activate ERα.

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Estrogen Causes Breast Cancer
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Henderson, Brian E., R. K. Ross, and Leslie Bernstein. “Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture.” Cancer research 48.2 (1988): 246-253.

https://joe.bioscientifica.com/downloadpdf/journals/joe/183/1/1830091.xml
194) Turan, V. K., et al. “The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone.” Journal of endocrinology 183.1 (2004): 91-99.

Click to access Estrogen-carcinogenesis-in-breast-cancer-James-Yager-New-England-Journal-of-Medicine-2006.pdf-New-England-Journal-of-Medicine-2006.pdf

Yager, James D., and Nancy E. Davidson. “Estrogen carcinogenesis in breast cancer.” New England Journal of Medicine 354.3 (2006): 270-282.

conclusions

Studies of breast cancer have consistently found an increased risk associated with elevated blood levels of endogenous estrogen, clinical indicators of persistently elevated blood estrogen levels, and exposure to exogenous estrogen plus progestin through hormone-replacement therapy and the use of oral contraceptives. In experimental animals, estrogen treatment leads to the development of mammary tumors. Together, these observations support the hypothesis that estrogen is a mammary-gland carcinogen.
The mechanisms through which estrogens contribute to each phase of the carcinogenic process (initiation, promotion, and progression) are complex. The evidence suggests the participation of genotoxic estrogen metabolites and estrogen-receptor–mediated genomic and nongenomic signaling that affect cell proliferation and apoptosis in mammary tissue. The extent to which these two pathways
contribute to estrogen-mediated carcinogenesis and the ways by which genetic polymorphisms and environmental factors modify the effects of these pathways require further exploration. Even so, knowledge of the central role of estrogen in breast cancer has already led to the development of new preventive and therapeutic interventions that block receptor function or drastically reduce the levels of endogenous estrogen through the inhibition of its synthesis. The development of additional strategies on the basis of the inhibition of estrogen metabolism, inactivation of the reactive quinones, and specific inhibition of membrane estrogen-receptor– activated second-messenger pathways will probably lead to the availability of additional effective intervention approaches.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1832080/
Russo, J. I. H. R., and Irma H. Russo. “The role of estrogen in the initiation of breast cancer.” The Journal of steroid biochemistry and molecular biology 102.1-5 (2006): 89-96.

17-β-estradiol is able to induce complete neoplastic transformation of human breast epithelial cells, as proven by the formation of tumors in SCID mice. This model demonstrates a sequence of chromosomal changes that correlates with specific stages of neoplastic progression. The data also support the concept that 17-β-estradiol can act as a carcinogenic agent without the need of the ERα, although we cannot rule out thus far the possibility that other receptors such as ERβ, or other mechanisms could play a role in the transformation of human breast epithelial cells. These are areas of active research in our laboratory. The knowledge that breast cancer in women is associated with prolonged exposure to high levels of estrogens gives relevance to this model of estrogen induced carcinogenesis (6,8-10,15,16). For this reason this model is extremely valuable for furthering our understanding of estrogen induced carcinogenicity.