Needless Fear of Estrogen Replacement for Menopause
by Jeffrey Dach MD
Bioidentical Hormones could have saved 50,000 Lives according to Dr. Philip Sarrel Professor of OB/Gyne at Yale Medical School.
Dr Cathleen Rivera followed 1,000 Pre-Menopausal women (under age 45) after hysterectomy, and found that removal of the ovaries resulted in a disturbing 84% increase in death from heart disease. However, if these women were given estrogen replacement after ovarian removal, they were protected with a 35% decrease in mortality from heart disease. I thought this was rather impressive.
The 2nd arm of the Women’s Health Initiative also showed reduced mortality in the estrogen users (50-59 yrs) after hysterectomy. They showed a 27% reduction in mortality with estrogen use. So this supports the hypothesis that estrogen deficiency is associated with increased mortality and other health risks, while estrogen replacement for post-hysterectomy women is very beneficial. Of course, women should avoid Progestins and other synthetic hormones such as medroxyprogesterone (MPA) which is known to be carcinogenic from the First Arm WHI data. The use of natural, bioidentical estrogen and progesterone in the proper balance is the preferred choice. Bioidentical hormones are not chemically altered, having chemical structures identical to our own hormones, naturally occurring in ourselves.
According to a new study, fifty thousand women died needlessly because of fear of estrogen replacement after hysterectomy. Hysterectomy causes estrogen deficiency, a heath risk associated with increased mortality. Both Time Magazine and the LA Times declared 50,000 women’s lives could have been saved.(3-5)
Header image: Photograph of Greta Garbo, courtesy of Wikimedia commons.
The Mortality Toll of Estrogen Avoidance Dr. Phillip Sarrel Professor of Ob/Gyne at Yale University
Dr Phillip M. Sarrel says: “Estrogen therapy has been widely misunderstood, and may offer important benefits to women in their 50s who have had a hysterectomy.” Watch this video from Philip M. Sarrel, MD , professor of Obstetrics and Gynecology at Yale Medical School.(3)
This information is old news. For many years, medical studies show HRT after hysterectomy reduces mortality and improves quality of life.
Bioidentical Estrogen Hormones Reduce Mortality After Hysterectomy
For example, Dr. Parker followed 30,000 women over 24 years after hysterectomy. Half the women had ovaries removed and half had ovaries preserved. The group with ovaries removed had estrogen deficiency, and higher all cause mortality rate. Therefore, Dr. Parker recommended ovarian preservation.
Dr Parker also found that post-operative hormone replacement is very beneficial for reducing heart disease risk in women after hysterectomy. (1)
In a second study, Dr Cathleen Rivera followed 1,000 Pre-Menopausal women, under age 45, after hysterectomy, and found that removal of the ovaries resulted in a disturbing 84% increase in death from heart disease. However, if these women were given estrogen replacement after ovarian removal, they were protected with a 35% decrease in mortality from heart disease.(2) I thought this was rather impressive.
The Second Arm of the Women’s Health Initiative showed reduced mortality in the Estrogen users after hysterectomy. (11)
For the Premarin treated post-menopausal women 50-59 years of age, the authors reported an impressive 27% reduction in mortality compared to placebo group. (11) The obvious take-home message is that estrogen replacement is beneficial for women after hysterectomy. Doctors who deny women estrogen replacement cause needless suffering and increased mortality. Left Image: Pregnant Horse source of Premarin courtesy of wikimedia commons
What about Menopausal Hormone Replacement?
Estrogens Users Had 27% Decrease in Mortality
Here is the quote from the 2011 JAMA publication of the Women’s Health Initiative (8):
Younger postmenopausal women (aged 50-59 years) who were randomized to Premarin estrogen (CEE) vs. placebo had a lower risk of death (HR, 0.73) Note: HR is Hazard Ratio.
This represents a 27% decrease in mortality for the estrogen users compared to placebo users (8)
The Fear of Breast Cancer from Hormone Therapy
In 2022, Dr. Tan and Dayu conclude that fear of breast cancer associated with menopausal hormone replacement applies to is no longer valid, as increased breast cancer risk applies only to estrogen/progestin (i.e. medroxyprogesterone MPA) and not to estrogen alone, nor the combination of estrogen/progesterone (bioidentical hormones). Dr Tan writes:
The threat that women may develop breast cancer is the major reason why both physicians and women are afraid to use menopausal hormone therapy (MHT). The fear pertains to estrogen-progestin [medroxyprogesterone] replacement therapy (EPRT) as estrogen-alone replacement therapy has no, or even a reduced, breast cancer risk… and avoiding MHT use when indicated puts a woman in harm’s way. (19)
The MPA Animal Model of Breast Cancer
The progestin, MPA (medroxyprogesterone) is a known carcinogen. In fact, cancer researchers commonly use MPA to induce breast cancer in mice. (28-43)
Women’s Health Initiative Study 11.8 years Follow Up
23% Reduction in Breast Cancer in Estrogen Users
In 2012, Drs. Garnet L Anderson PhD, and Rowan T Chlebowski reported the data on the 11.8 year follow up of the WHI study, the second arm consisting of women who had hysterectomy and were treated with premarin alone. After 11.8 years of follow up, the Premarin (horse estrogen) had 151 cases of invasive breast cancer and the placebo group had 199 cases. This represents a 23% reduction in breast cancer in the estrogen treated group. In 2012, Drs. Anthony Howell, and Jack Cuzick commented on the above study, writing:
In The Lancet Oncology, the Women’s Health Initiative (WHI) investigators report 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. (44-45)
Avoid Carcinogenic Synthetic Progestins
Synthetic versions of progesterone called “Progestins” such as medroxyprogesterone (MPA) are known to be carcinogenic based on data from the 2002 Womens Health Initiative WHI First Arm.(12) This study was halted early because synthetic progestins increased the risk of breast cancer. For this reason, avoiding carcinogenic progestins is recommended. Instead, use natural human bioidentical progesterone having the same chemical structure as ovarian progesterone, made by the female ovary.
Dr. JoAnn Mason is in Agreement.
In 2016, Dr. JoAnn E. Manson’s wrote an editorial in the New England Journal of Medicine about the sad state of affairs in our medical system regarding menopausal hormone replacement. Dr. JoAnn Manson writes:
Despite the availability of effective hormonal …treatments for menopausal symptoms, few women with these symptoms are evaluated or treated…Leading medical societies …agree that hormone therapy is the most effective treatment currently available for (menopausal) symptoms and should be recommended…Yet, “20% of women in early menopause… remain untreated despite having symptoms that adversely affect their daily activities, sleep, and quality of life… the new generation of …primary care providers often lacks training and core competencies in management of menopausal symptoms and prescribing of hormonal …treatments…Reluctance to treat menopausal symptoms has derailed and fragmented the clinical care of midlife women, creating a large and unnecessary burden of suffering.(10)
2017 Calcium Score Study From Cedars Sinai Presented at
ACC 66th Annual Meeting.
Women using hormone replacement therapy were:
1) Thirty percent less likely to die than those not on hormone therapy. 2) Twenty percent more likely to have a coronary calcium score of zero (the lowest possible score, indicating a low likelihood of heart attack) 3) Thirty-six percent less likely to have a coronary calcium score that indicates extensive atherosclerosis and a 10-fold increase in heart attack risk.(15-17)
We have known for decades the benefits of estrogen replacement after hysterectomy. Yet, thousands of women have been denied estrogen replacement causing needless suffering. Our stated mission at TrueMedMD is offer bioidentical hormones for all post menopausal women requesting it.
Articles with Related Interest:
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
1) Parker, William H., et al. “Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study.” Obstetrics and gynecology 113.5 (2009): 1027.
OBJECTIVE: To report long-term health outcomes and mortality after oophorectomy or ovarian conservation.
METHODS: We conducted a prospective, observational study of 29,380 women participants of the Nurses’ Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy, and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes.
RESULTS: Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy compared with ovarian conservation, the multivariable hazard ratios (HRs) were1.12 (95% confidence interval [CI] 1.03-1.21) for total mortality, 1.17 (95% CI 1.02-1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98-1.33) for stroke. Although the risks of breast (HR 0.75, 95% CI 0.68-0.84), ovarian (HR 0.04, 95% CI 0.01-0.09, number needed to treat=220), and total cancers (HR 0.90, 95% CI 0.84-0.96) decreased after oophorectomy, lung cancer incidence (HR=1.26, 95% CI 1.02-1.56, number needed to harm=190), and total cancer mortality (HR=1.17, 95% CI 1.04-1.32) increased.
For those never having used estrogen therapy, bilateral oophorectomy before age 50 years was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span after surgery, one additional death would be expected for every nine oophorectomies performed.
CONCLUSION: Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer but an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer. In no analysis or age group was oophorectomy associated with increased survival.
2) Rivera, Cathleen M., et al. “Increased cardiovascular mortality following early bilateral oophorectomy.” Menopause (New York, NY) 16.1 (2009): 15.
We conducted a cohort study with long-term follow-up of women in Olmsted County, MN, who underwent either unilateral or bilateral oophorectomy before the onset of menopause from 1950 through 1987. Each member of the oophorectomy cohort was matched by age to a referent woman from the same population who had not undergone any oophorectomy. We studied the mortality associated with cardiovascular disease in a total of 1,274 women with unilateral oophorectomy, 1,091 women with bilateral oophorectomy, and 2,383 referent women.
Results: Women who underwent bilateral oophorectomy before age 45 years experienced anincreased mortality associated with cardiovascular disease compared with referent women (HR, 1.44; 95% CI, 1.01–2.05; P = 0.04).
Within this age stratum, the HR for mortality was significantly elevated in women who were not treated with estrogen through age 45 years or longer (HR, 1.84; 95% CI, 1.27–2.68; P = 0.001) but not in women treated (HR, 0.65; 95% CI, 0.30–1.41; P = 0.28; test of interaction, P = 0.01). Mortality was further increased after excluding deaths associated with cerebrovascular causes.
Conclusions: Bilateral oophorectomy performed before age 45 years is associated with increased cardiovascular mortality, especially with cardiac mortality. However, estrogen treatment may reduce this risk.
From a clinical perspective, our findings suggest that women who underwent bilateral oophorectomy at a young age are at increased risk of cardiovascular death, especially of cardiac death. This increased mortality may be attenuated by adequate estrogen treatment. Our findings provide new evidence to guide the individualized assessment of the risks and benefits of prophylactic bilateral oophorectomy in young women.1,4–6,8,14 This preventive practice currently involves approximately 4.5 million women older than 55 years living in the United States who have undergone bilateral oophorectomy before reaching natural menopause.28,34
In addition, our findings provide observational evidence for a long-term cardiovascular protective effect of estrogen either naturally produced by the ovaries or given as treatment to women who underwent bilateral oophorectomy at younger ages. These findings emphasize the importance of estrogen treatment after the surgery.6,9–14
We focused our analyses on age at estrogen deficiency rather than on the length of estrogen treatment after the surgery to study the combined effects of age at the surgery and length of treatment.
Several studies have shown increased cardiovascular mortality in women who experienced early menopause (before age 45 years) from either natural or medical causes,35–40 and a statistical model has linked prophylactic bilateral oophorectomy before age 65 years with an increase in overall mortality and coronary heart disease mortality.1,4,5
Similarly, in the Women’s Health Initiative Observational Study, hysterectomy plus oophorectomy performed over a broad age range was a significant predictor of cardiovascular disease during a short-term follow-up.28
Recent analyses from the Women’s Health Initiative Coronary Artery Calcium Study showed an increased risk of subclinical coronary artery disease in women who underwent both hysterectomy and bilateral oophorectomy and were not treated with estrogen compared to women who underwent hysterectomy alone. The increased risk was independent of traditional cardiovascular risk factors.12
Our results for estrogen treatment after bilateral oophorectomy are consistent both with findings from previous clinical studies40–44 and with findings from animal studies. Primates who underwent premenopausal oophorectomy and did not receive exogenous estrogen had significantly accelerated atherosclerosis compared with those that did not have oophorectomy
This study showed that women who underwent early bilateral oophorectomy are at increased risk of death involving cardiovascular disease, especially cardiac diseases. However, treatment with estrogen through age 45 years or longer may reduce this risk. These findings, in conjunction with the results of other studies,1,4,5,8 have important clinical implications and should prompt a reassessment of prophylactic bilateral oophorectomy in premenopausal women.6,14
3) Sarrel, Philip M., et al. “The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years.” American journal of public health 103.9 (2013): 1583-1588.
Objectives. We examined the effect of estrogen avoidance on mortality rates among hysterectomized women aged 50 to 59 years.
Methods. We derived a formula to relate the excess mortality among hysterectomized women aged 50 to 59 years assigned to placebo in the Women’s Health Initiative randomized controlled trial to the entire population of comparable women in the United States, incorporating the decline in estrogen use observed between 2002 and 2011.
Results. Over a 10-year span, starting in 2002, a minimum of 18 601 and as many as 91 610 postmenopausal women died prematurely because of the avoidance of estrogen therapy (ET).
Conclusions. ET in younger postmenopausal women is associated with a decisive reduction in all-cause mortality, but estrogen use in this population is low and continuing to fall. Our data indicate an associated annual mortality toll in the thousands of women aged 50 to 59 years. Informed discussion between these women and their health care providers about the effects of ET is a matter of considerable urgency. (Am J Public Health. Published online ahead of print July 18, 2013:)
4) Hormone-Replacement Therapy: Could Estrogen Have Saved 50,000 Lives? By Alexandra Sifferlin July 20, 2013 Time Magazine
Dr. Philip Sarrel, professor emeritus of obstetrics, gynecology and reproductive sciences at Yale University School of Medicine and lead author of the study, said in a video discussing the study that none of these women, who were aged 50 to 59 at the start of the study, lived to reach their 70s. Most died of heart disease, bolstering the connection that earlier studies had found between estrogen-only therapy and a lower risk of heart problems among women who had a hysterectomy.
5) Avoiding estrogen therapy proved deadly for nearly 50,000: study
By Eryn Brown July 18, 2013, LA Times
6) Huffington Post – David Katz, M.D. Director, Yale Prevention Research Center. Estrogen and Evidence Posted: 07/23/2013 2:48 pm
7) Did Avoidance of Hormone Therapy Harm Certain Women?
For older women without a uterus, estrogen may save lives, researchers say: The use of hormone therapy — both estrogen-only and the combination of estrogen plus progestin — declined greatly after the U.S. Women’s Health Initiative Study found in 2002 that combination therapy had ill effects, including an increase in breast cancer, heart disease, stroke and blood clots. Prescriptions for both regimens plummeted even though the research didn’t apply to women without a uterus or to women on estrogen-only therapy, said Sarrel, who is a consultant for Noven Therapeutics, which makes an estrogen patch.
They found that use of estrogen-only therapy in U.S. women aged 50 to 59 declined nearly 79 percent between 2001 and 2011.
During that time, at least 18,000 excess deaths occurred because of estrogen avoidance and possibly more than 91,000, depending on the calculations used, Sarrel’s team said. For this reason, their best estimate — of about 50,000 deaths — may be conservative, said Sarrel.
8) 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. Health outcomes after conjugated equine estrogens postmenopausal women with hysterectomy LaCroix Andrea Jama 2011
The HRs for total mortality and the global index of chronic diseases differed by age as previously suggested.7
Younger postmenopausal women (aged 50-59 years) who were randomized to CEE vs placebo had a lower risk of death (0.35% [n = 65] vs 0.48% [n = 89], respectively; HR, 0.73 [95% CI, 0.53-1.00]) compared with no increased risk among women in their 60s (1.00% [n = 254] vs 0.96% [n = 253], respectively; HR, 1.04 [95% CI, 0.88-1.24]), and a slight increased risk of death among women in their 70s (2.02% [n = 258] vs 1.83% [n = 239], respectively; HR, 1.12 [95% CI, 0.94-1.33]; P = .04 for interaction). A similar pattern was observed by age for women randomized to CEE vs placebo for the global index of chronic diseases with a possible overall benefit among younger women (aged 50-59 years: 1.04% [n = 184] vs 1.22% [n = 217], respectively; HR, 0.85 [95% CI, 0.70-1.03]) and possible harm among the oldest women (aged 70-79 years: 4.04% [n = 466] vs 3.56% [n = 423], respectively; HR, 1.15 [95% CI, 1.01-1.32]; P = .009 for interaction).
10) Manson, JoAnn E., and Andrew M. Kaunitz. “Menopause Management—Getting Clinical Care Back on Track.” New England Journal of Medicine 374.9 (2016): 803-806. menopause-management-getting-clinical-care-back-on-track-new-england-journal-manson-joann-2016
11) Anderson, G. L., et al. “Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial.” Jama 291.14 (2004): 1701-1712.
12) 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) American College of Cardiology Press release
Hormone Replacement Therapy Associated with Lower Mortality
Therapy also linked with less plaque buildup in the heart’s arteries Mar 08, 2017
Arnson will present the study, “Hormone Replacement Therapy Is Associated With Less Coronary Atherosclerosis and Lower Mortality,” on Friday, March 17, at 3:45 p.m. ET at the Non Invasive Imaging Moderated Poster Theater, Poster Hall C at the American College of Cardiology’s 66th Annual Scientific Session in Washington. The meeting runs March 17-19. – See more at: http://www.acc.org/about-acc/press-releases/2017/03/08/13/09/hormone-replacement-therapy-associated-with-lower-mortality#sthash.8UF3tn0w.dpuf
16) Study: Hormone Replacement Therapy May Help Improve Women’s Heart Health, Overall Survival Cedars-Sinai Study Suggests the Treatment Is Also Linked With Less Plaque Buildup in the Heart’s Arteries. Contact Nilou Salimpour Los Angeles — March 8, 2017
women using hormone replacement therapy were:
Thirty percent less likely to die than those not on hormone therapy
Twenty percent more likely to have a coronary calcium score of zero (the lowest possible score, indicating a low likelihood of heart attack)
Thirty-six percent less likely to have a coronary calcium score that indicates extensive atherosclerosis and a 10-fold increase in heart attack risk
17) Hormone replacement therapy associated with lower early mortality
Date: March 8, 2017 Source: American College of Cardiology
Summary: Women using hormone replacement therapy to relieve the symptoms of menopause faced a lower risk of death and showed lower levels of atherosclerosis, or plaque buildup in the heart’s arteries, compared to women not using hormone therapy, according to a single-center study.
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18) Palacios, Santiago, et al. “Hormone therapy for first-line management of menopausal symptoms: Practical recommendations.” Women’s Health 15 (2019): 1745506519864009.
Hormone therapy use has undergone dramatic changes over the past 20 years. Widespread use of hormone therapy in the 1980s and 1990s came to an abrupt halt in the early 2000s after initial findings of the Women’s Health Initiative trial were published and the study was terminated. Since then, much has been learned about the characteristics of women most likely to benefit from hormone therapy. There is general agreement that women younger than 60 years
or who initiate hormone therapy within 10 years of menopause onset gain short-term benefit in terms of symptomatic relief and long-term benefit in terms of protection from chronic diseases that affect postmenopausal women. Despite accumulating evidence in support of hormone therapy for symptomatic menopausal women, the slow response by the medical community has led to a ‘large and unnecessary burden of suffering’ by women worldwide. Greater efforts are clearly needed to educate physicians and medical students about the pathophysiology of menopause and the role of hormone therapy in supporting women through the transition. This article provides a brief historical perspective of events that led to the backlash against hormone therapy, explores the current position of guideline groups, and provides practical recommendations to guide first-line management of symptomatic menopausal women.
19) Tan, D. A., and A. R. B. Dayu. “Menopausal hormone therapy: why we should no longer be afraid of the breast cancer risk.” Climacteric 25.4 (2022): 362-368.
The threat that women may develop breast cancer is the major reason why both physicians and women are afraid to use menopausal hormone therapy (MHT). The fear pertains to estrogen-progestin replacement therapy (EPRT) as estrogen-alone replacement therapy has no, or even a reduced, breast cancer risk. We reviewed the way breast cancer risk with EPRT was reported in some major publications since 2002 and tried to put the use-risk association in context. We hope this will make it easier for the physician and the menopausal woman to understand the risk involved and allow more confident and more informed decision-making regarding MHT use. We conclude that there are five interrelated reasons why physicians and women should no longer be afraid of the breast cancer risk with EPRT. We submit that breast cancer related to EPRT use is rare because the risk is very low; the reported increase in breast cancer risk with EPRT is not relevant to current practice; modifiable lifestyle factors, not EPRT, are the real risks for breast cancer; breast cancer-specific mortality is reduced in women who develop breast cancer while on EPRT; and avoiding MHT use when indicated puts a woman in harm’s way.
20) Mei, Yixue, et al. “Roles of Hormone Replacement Therapy and Menopause on Osteoarthritis and Cardiovascular Disease Outcomes: A Narrative Review.” Frontiers in Rehabilitation Sciences (2022): 45.
21) Rozenberg, Serge, et al. “Breaking down barriers for prescribing and using hormone therapy for the treatment of menopausal symptoms: an experts’ perspective.” Expert review of clinical pharmacology: 1-11.
Introduction: Around 80% of women suffer menopause-related symptoms that affect their daily activities and quality of life. Menopausal hormone therapy (MHT) has proven to be beneficial in relieving these symptoms. Nevertheless, only 20/30% of symptomatic women seek treatment. This has resulted in neglect of a generation of healthcare professionals’ (HCPs) education in menopausal medicine and a reduction in the prescription of MHT in menopausal women for over two decades.
Areas covered: The aim of this article was to identify the main barriers that HCPs face for prescribing MHT and menopausal women for using it. Six European experts in menopause agreed on the profiles of women that benefit from MHT and proposed strategies to break down these barriers.
Expert opinion: The most important barrier for HCPs was deficient knowledge of the true evidence-based information, with inadequate training regarding the efficacy and safety of personalized MHT and the real benefit/risk ratio in the treatment of symptomatic women. For patients, fear of developing breast cancer was identified as the single most important barrier.
22) Faubion, Stephanie S., and Chrisandra Shufelt. “The Menopause Management Vacuum.” Cancer journal (Sudbury, Mass.) 28.3 (2022): 191-195.
The burden of untreated menopause symptoms in midlife women is substantial and can result in reduced quality of life as well as lost work productivity, lost opportunities for advancement at work, and increased health care costs. Unfortunately, the health care system is largely unprepared to help women manage these symptoms, which have a mean duration of 7 to 9 years. Hormone therapy usage rates have plummeted following publication of the results of the Women’s Health Initiative trials due to safety concerns. In addition, postgraduate medical training programs include minimal to no training on menopause management. These and other factors have contributed to what is essentially a menopause management vacuum. This vacuum created a market opportunity, particularly given the fact that midlife women are potent drivers of the global economy. In this review, we outline the menopause management gaps and discuss a multipronged approach to close these gaps and improve the care of midlife women.
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23) Sarrel, Philip M. “A call to increase the use of hormone therapy to prevent disease in symptomatic postmenopausal women.” Menopause 26.6 (2019): 573-575. Editorial
23) Natural (Bioidentical) vs. Synthetic Hormone Replacement Therapy
by Kent Holtorf, MD
24) Estrogen Vindication, Part 1: Estrogen and the WHI
By Devaki Lindsey Berkson, DC
25) Estrogen Vindication, Part 2: Estrogen, Cancer Stem Cells, and Studies By Devaki Lindsey Berkson, DC
26) Estrogen Vindication, Part 3: The Tamoxifen Connection and Hormone Therapy by Devaki Lindsey Berkson, DC
The appreciation of estrogen as “foundational” in protecting many aspects of health, is rapidly growing. A few examples are: estrogen protects bones from fracture,19 blood vessels from hardening,20 brain from dementia,21,22 shields mitochondria (energy-producing cells) from damage,23 allows bodies to benefit from lifestyle changes as it promotes epigenetics,24 makes it easier to keep a smaller waistline,25 and maintains heart26 and kidney27-29 health.
The Benefits of Estrogen
By the early 1990s, researchers had summarized the benefits of estrogen therapies and documented them in the medical literature.
· Estrogen controls menopausal symptoms.
· If given early, it helps prevent strokes and bone loss and fractures for many years, even after discontinuation.
· Estrogen significantly reduces the risk of heart disease,85
· Estrogen significantly reduces the risk of fracture (Framingham study showed a 50% drop in osteoporosis-hip fracture),86
· Estrogen significantly decreases risk colorectal cancer,
· Estrogen significantly reduces the risk of cognitive decline and Alzheimer’s disease. The Cache County studies (which had the bad karma to come out only months after the WHI and was not noticed) showed that if women had been on 10 years of estrogen therapies, they had a 30 to 50% reduction in incidence of AD.
· Estrogen has now been found to have hundreds of other pleotropic effects, such as helping epigenetics87 and protecting mitochondria (our energy organelles) from damage,88 so it helps in maintaining the energy production needed for a positive lifestyle effort.
· Estrogen helps maintain volume, plasticity, and protection from injury of the hippocampus, where memories live in the brain.89
Now we see that estrogen protects against breast cancer in a woman who has not yet had it and even in those that already have.90,91 To age without individualized hormonal support is to age at the speed of an accelerating bullet, while hormonal therapies allow us to live younger longer and healthier.
27) Supporting Healthy Estrogen Metabolism During Bioidentical Hormone Replacement Therapy by Chris D. Meletis, ND, and Kimberly Wilkes
When implementing a bioidentical hormone replacement therapy regimen, it is essential to support the safe metabolism of estrogen. The gut is an important source of steroid hormones such as estrogen, and probiotic organisms play a role in how the gut metabolizes estrogens. A balanced gut microbiota also increases the effectiveness of phytoestrogen supplements such as soy. I3C and DIM are important supplements that ensure that estrogen is escorted out of the body through the safest possible pathway. Calcium-D-glucarate also assists with estrogen metabolism as it blocks an enzyme known as beta-glucuronidase, which interferes with the body’s ability to safely process estrogen and potentially harmful substances such as drugs and toxins. Additionally, mitochondrial support also is recommended during hormone replacement therapy, as all hormones originate in the mitochondria, which possess steroid hormone receptors.
28) Lanari, Claudia Lee Malvina, et al. “The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer.” (2009). The MPA mouse breast cancer model Lanari Claudia 2009
29) Aldaz, C. Marcelo, et al. “Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene.” Carcinogenesis 17.9 (1996): 2069-2072. Medroxyprogesterone MPA accelerates mouse mammary tumors induced by dimethylbenzanthracene DMBA Aldaz Marcelo
30) Lanari, Claudia, Alfredo A. Molinolo, and Christiane Dosne Pasqualini. “Induction of mammary adenocarcinomas by medroxyprogesterone acetate in BALBc female mice.” Cancer letters 33.2 (1986): 215-223.
31) Lanari, Claudia, et al. “Mammary adenocarcinomas induced by medroxyprogesterone acetate: hormone dependence and EGF receptors of BALB/c in vivo sublines.” International journal of cancer 43.5 (1989): 845-850.
32) Molinolo, A. A., et al. “Mouse mammary tumors induced by medroxyprogesterone acetate: immunohistochemistry and hormonal receptors.” Journal of the National Cancer Institute 79.6 (1987): 1341-1350.
32) Molinolo, A. A., et al. “Mouse mammary tumors induced by medroxyprogesterone acetate: immunohistochemistry and hormonal receptors.” Journal of the National Cancer Institute 79.6 (1987): 1341-1350.
33) Nagasawa, Hiroshi, et al. “Medroxyprogesterone acetate enhances spontaneous mammary tumorigenesis and uterine adenomyosis in mice.” Breast cancer research and treatment 12 (1988): 59-66.
34) Liang, Yayun, et al. “Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice.” Menopause (New York, NY) 17.5 (2010): 1040.
35) Kordon, Edith, et al. “Hormone dependence of a mouse mammary tumor line induced in vivo by medroxyprogesterone acetate.” Breast cancer research and treatment 17 (1990): 33-43.
36) Montecchia, Marı́a Fernanda, et al. “Progesterone receptor involvement in independent tumor growth in MPA-induced murine mammary adenocarcinomas.” The Journal of Steroid Biochemistry and Molecular Biology 68.1-2 (1999): 11-21.
37) Helguero, Luisa A., et al. “Progesterone receptor expression in medroxyprogesterone acetate-induced murine mammary carcinomas and response to endocrine treatment.” Breast Cancer Research and Treatment 79 (2003): 379-390.
38) Sartorius, Carol A., et al. “Progestins initiate a luminal to myoepithelial switch in estrogen-dependent human breast tumors without altering growth.” Cancer research 65.21 (2005): 9779-9788.
39) Kordon, Edith C., et al. “Progesterone induction of mammary carcinomas in BALB/c female mice: correlation between progestin dependence and morphology.” Breast cancer research and treatment 28 (1993): 29-39.
40) Pazos, Patricia, et al. “Mammary carcinogenesis induced by N-methyl-N-nitrosourea (MNU) and medroxyprogesterone acetate (MPA) in BALB/c mice.” Breast cancer research and treatment 20 (1991): 133-138.
41) Molinolo, Alfredo, et al. “Involvement of EGF in medroxyprogesterone acetate (MPA)-induced mammary gland hyperplasia and its role in MPA-induced mammary tumors in BALB/c mice.” Cancer letters 126.1 (1998): 49-57.
42) Kordon, Edith, et al. “Estrogen inhibition of MPA‐induced mouse mammary tumor transplants.” International journal of cancer 49.6 (1991): 900-905.
43) Buqué, Aitziber, et al. “MPA/DMBA-driven mammary carcinomas.” Methods in Cell Biology. Vol. 163. Academic Press, 2021. 1-19.
44) 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.
45) 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 report 1 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==============================================================================
Stute, Petra, et al. “Reappraising 21 years of the WHI study: Putting the findings in context for clinical practice.” Maturitas (2023).
Jordan, V. Craig. “Molecular mechanism for breast cancer incidence in the Women’s Health Initiative.” Cancer Prevention Research 13.10 (2020): 807-816.
Graham, Shelli, et al. “Review of menopausal hormone therapy with estradiol and progesterone versus other estrogens and progestins.” Gynecological endocrinology: the official journal of the International Society of Gynecological Endocrinology 38.11 (2022): 891-910.
Objective: The objective of the present document was to review/summarize reported outcomes compared between menopausal hormone therapy (MHT) containing estradiol (E2) versus other estrogens and MHT with progesterone (P4) versus progestins (defined as synthetic progestogens).Methods: PubMed and EMBASE were systematically searched through February 2021 for studies comparing oral E2 versus oral conjugated equine estrogens (CEE) or P4 versus progestins for endometrial outcomes, venous thromboembolism (VTE), cardiovascular outcomes, breast outcomes, cognition, and bone outcomes in postmenopausal women.Results: A total of 74 comparative publications were identified/summarized. Randomized studies suggested that P4 and progestins are likely equally effective in preventing endometrial hyperplasia/cancer when used at adequate doses. E2- versus CEE-based MHT had a similar or possibly better risk profile for VTE and cardiovascular outcomes, and P4- versus progestin-based MHT had a similar or possibly better profile for breast cancer and cardiovascular outcomes. E2 may potentially protect better against age-related cognitive decline and bone fractures versus CEE; P4 was similar or possibly better versus progestins for these outcomes. Limitations are that many studies were observational and some were not adequately powered for the reported outcomes.Conclusions: Evidence suggests a differential effect of MHT containing E2 or P4 and those containing CEE or progestins, with some evidence trending to a potentially better safety profile with E2 and/or P4.
Fenton, Anna. “The demise of HRT? The long-term safety of hormone replacement therapy.” Expert Opinion on Drug Safety 2.4 (2003): 341-345.
Hoffman, Ariel, Robert Powell, and Tyler R. Reese. “Increased risk for breast cancer with synthetic progestin HRT for menopausal symptoms.” Evidence-Based Practice (2023): 10-1097.
Lambrinoudaki, Irene. “Menopausal hormone therapy and breast cancer risk: all progestogens are not the same.” Case Reports in Women’s Health 29 (2021).
Horwitz, Kathryn B., and Carol A. Sartorius. “90 years of progesterone: progesterone and progesterone receptors in breast cancer: past, present, future.” Journal of Molecular Endocrinology 65.1 (2020): T49-T63.
Here we summarize the early history of PR in breast cancer; debunk the theory that progesterone causes cancer; discuss recent discoveries that PR regulate cell heterogeneity; attempt to unify theories describing PR as either good or bad actors in tumors; and discuss emerging areas of research that may help explain this enigmatic hormone and receptor.
It was originally assumed that, for MHT, progestins would counteract any tumor-promoting effects of estrogens in the breast, akin to their protective effects in the uterus (Gambrell et al. 1983). This was despite studies in rodents which suggested otherwise (Huggins 1965, Lydon et al. 1999). For instance, mice given chronic long-term MPA develop mammary tumors with high frequency (Lanari et al. 2009).
This was especially pronounced for long-term (>10 year) progestin users, who had twice the risk of developing breast cancer. Notably, this meta-analysis did not include bioidentical progesterone formulations, which had either no additional risk or even decreased breast cancer risk (discussed in Piette 2018). This has led to speculation that the androgenic and glucocorticoid activity of MPA and other progestins are responsible for the increased breast cancer risk (Carroll et al. 2017, Piette 2018).
Furthermore, it is important to distinguish between progestins and natural progesterone. Currently these tend to be lumped together leading to the view that progesterone is ‘carcinogenic’ (i.e. cancer causer). It is our opinion that natural progesterone does not ‘cause’ breast cancer but can expand it (see subsequent section). Hence, despite widespread linkage between the terms ‘progestins’ and ‘carcinogenesis’, we suggest that care must be taken with these ideas, as with the term ‘bioidentical’, until solid data are available, in women, differentiating between the natural hormone and any biosynthetic ones.
First, we need to debunk the notion that progesterone ‘causes’ breast cancers. There is considerable experimental and clinical evidence that, alone and at physiological levels, progesterone is incapable of causing breast cancers so that its reputation as a ‘tumorigenic’ or ‘carcinogenic’ hormone is undeserved. It would be useful to have definitive proof of this once and for all and to eliminate use of these terms in reference to progesterone and the breast.
Coelingh Bennink, Herjan JT, et al. “Progesterone from ovulatory menstrual cycles is an important cause of breast cancer.” Breast Cancer Research 25.1 (2023): 1-16.
We propose to develop medical strategies in women that avoid exposure to natural P4 and progestins as much as possible.
We therefore postulate that P4 is an important factor in a woman’s lifetime risk of developing BC, and that breast tumors arising during hormonal contraception or after menopause, with or without menopausal hormone therapy, are the consequence of the outgrowth of pre-existing neoplastic lesions, eventually stimulated by estrogens and some progestins.
Abenhaim, Haim A., et al. “Menopausal Hormone Therapy Formulation and Breast Cancer Risk.” Obstetrics and gynecology 139.6 (2022): 1103-1110.
Objective: To evaluate whether the increased risk of breast cancer is dependent on the formulation of menopausal hormone therapy (HT) used.
Methods: We performed a population-based case-control study of women aged 50 years or older using data from the U.K. Clinical Practice Research Datalink. Women with incident cases of breast cancer were age-matched (1:10) with a control group of women with comparable follow-up time with no history of breast cancer. Exposures were classified as ever or never for the following menopausal HT formulations: bioidentical estrogens, animal-derived estrogens, micronized progesterone, and synthetic progestin. Logistic regression analyses were performed to estimate the adjusted effect of menopausal HT formulation on breast cancer risk.
Results: Between 1995 and 2014, 43,183 cases of breast cancer were identified and matched to 431,830 women in a control group. In adjusted analyses, compared with women who never used menopausal HT, its use was associated with an increased risk of breast cancer (odds ratio [OR] 1.12, 95% CI 1.09-1.15). Compared with never users, estrogens were not associated with breast cancer (bioidentical estrogens: OR 1.04, 95% CI 1.00-1.09; animal-derived estrogens: OR 1.01, 95% CI 0.96-1.06; both: OR 0.96, 95% CI 0.89-1.03). Progestogens appeared to be differentially associated with breast cancer (micronized progesterone: OR 0.99, 95% CI 0.55-1.79; synthetic progestin: OR 1.28, 95% CI 1.22-1.35; both OR 1.31, 0.30-5.73).
Conclusion: Although menopausal HT use appears to be associated with an overall increased risk of breast cancer, this risk appears predominantly mediated through formulations containing synthetic progestins. When prescribing menopausal HT, micronized progesterone may be the safer progestogen to be used.
Lambrinoudaki, Irene. “Menopausal hormone therapy and breast cancer risk: all progestogens are not the same.” Case Reports in Women’s Health 29 (2021).
Vinogradova et al.  preformed a large case-control study using two large UK general practice databases with the objective to assess breast cancer risk associated with different types and durations of MHT. 98,611 women aged 50–79 with breast cancer were matched to 457,398 control women, based on age, general practice and index date. Estrogen-only therapy for up to 9 years increased only marginally the risk of breast cancer (OR 1.14, CI 1.08–1.21), whereas estrogen–progestin combination therapy for the same duration was associated with a more pronounced increase in breast cancer risk (OR 1.70, CI 1.64 to 1.76). The risk differed according to the progestin used, being higher with medroxyprogesterone acetate, levonorgestrel and norethisterone (OR 1.87 CI 1.71 to 2.05, 1.79 CI 1.68 to 1.90 and 1.88 CI 1.79 to 1.99 respectively) and lower with dydrogesterone (OR 1.24 CI 1.03 to 1.48) for more than 5 years of therapy. The excess risk dissipated in past users.
The study confirmed what we already knew from the WHI studies [4,5]: The excess risk of breast cancer associated with MHT is mainly conferred by the progestin.
Jeffrey Dach MD
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